Electrical impedance properties of normal and chronically infarcted left ventricular myocardium.

Editor's evaluation: Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart

B-AB03-03 PULSED FIELD ABLATION OF LEFT VENTRICULAR MYOCARDIUM IN A SWINE INFARCT MODEL

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): British Heart Foundation - Prof Marc Dweck Senior Fellowship, and BHF Research Excellence Award 3 for Dr Anna K Barton. Background Myocardial fibrosis is a key healing response following myocardial infarction (MI). Although scar formation following MI is considered complete by 12 weeks, its exact time course is unknown. Fibroblast activation protein is a key factor in fibrogenesis that is expressed by activated fibroblasts in the myocardium following MI. Hybrid positron emission tomography and cardiovascular magnetic resonance (PET/MR) with radiolabelled fibroblast activation protein inhibitor (68Ga-FAPI) is an emerging method to measure in vivo fibrosis activity. Purpose To investigate the timing of myocardial fibrosis activity following ST-elevation MI using 68Ga-FAPI PET/MR Methods Twenty patients underwent multi-timepoint hybrid 68Ga-FAPI PET/MR <1, 2, 4, and 12 weeks following acute ST-elevation MI. They were compared to patients with prior established ST-elevation MI (>12 months) and healthy controls who underwent single-timepoint 68Ga-FAPI PET/MR to determine fibrosis activity in chronic infarcts and healthy myocardium respectively. All participants were imaged 30 min following administration of 100–200 MBq 68Ga-FAPI-04. Infarct zone 68Ga-FAPI uptake was quantified using tissue-to-background ratio (TBRmax) after correction for blood-pool activity in the left ventricle. Comparisons between timepoints for the acute MI group were assessed by ANOVA with repeated measures and post hoc Bonferroni correction, and between groups by two-tailed t-test. Results Participants were predominantly middle-aged men (Table). Focal 68Ga-FAPI uptake localised to areas of infarction within the infarct and peri-infarct zones on late gadolinium enhancement on magnetic resonance imaging (Figure). In acute MI, there was substantial uptake with consistent TBRmax values at weeks 1, 2 and 4 (Table and Figure). Though TBRmax values started to decline by week 12 they remained persistently elevated compared to prior established MI and healthy myocardium (Table). Participants with prior established MI had modestly increased 68Ga-FAPI uptake compared with the healthy myocardium of control participants (Table and Figure). Conclusions Intense myocardial fibrosis activity is observed in the infarct and peri-infarct zones throughout the first month following ST-elevation MI. Although this starts to decline by 12 weeks, it remains markedly elevated even several years after myocardial infarction, indicating that low-level chronic fibroblast activity is a feature of established MI.

Pulsed-field ablation (PFA) is a nonthermal energy with higher selectivity to myocardial tissue in comparison to radiofrequency ablation (RFA). We compared the effects of PFA and RFA on heterogeneous ventricular scar in a swine model of healed infarction. In 9 swine, myocardial infarction was created by balloon occlusion of the left anterior descending artery. After a survival period of 8 to 10 weeks, ablation with PFA or RFA was performed at infarct border zones identified by abnormal electrograms. In the PFA group (4 swine), ablation was performed with a lattice catheter (Sphere-9, Affera, Inc). In the RFA group (5 swine), ablation was performed using a 3.5-mm tip catheter (Thermocool ST-SF; Biosense Webster). To further investigate the effect of RFA on temperature development in scar tissue, intramyocardial temperature was measured in healthy and infarcted myocardium using an ex vivo bath model. A total of 11 PFA and 15 RFA lesions were created at infarct border zones with heterogeneous scar. PFA produced uniform and well-demarcated lesions exhibiting irreversible injury characterized by cardiomyocyte death, contraction bands, and lymphocytic infiltration. This effect of PFA extended from the subendocardium through collagen and fat to the epicardial layers. In contrast, the effect of RFA is less uniform and largely limited to the subendocardium with minimal effect on viable myocardium deeper to separating layers of collagen and fat. PFA produced deeper and more transmural lesions (6.4 [interquartile range, 5.5-7.5) versus 5.4 [interquartile range, 4.8-5.9]), 72% versus 30%, respectively; P≤0.02 for each comparison). The limited effect of RFA on viable myocardium at deeper infarct layers was related to a lower intramyocardial maximal temperature compared with healthy myocardium (P=0.01). PFA may be advantageous for ablation in ventricular scar, producing lesions that unlike RFA are not limited to the subendocardium, but also eliminate viable myocardium separated from the catheter by collagen and fat.

Utility and Limitations of Ablation Index for Guiding Therapy in Ventricular Myocardium

Passive mechanical properties in healthy and infarcted rat left ventricle characterised via a mixture model

Discrimination of Myocardial Acute and Chronic (Scar) Infarctions on Delayed Contrast Enhanced Magnetic Resonance Imaging With Intravascular Magnetic Resonance Contrast Media

Atrial myocardial substrate has a significant influence on local impedance data - clinical experience from high power short duration and standard radio frequency ablations

Background Besides total scar size, scar characterization parameters are emerging as additional prognostic factors after acute myocardial infarction. Of these, microvascular obstruction (MVO) and infarct border zone are the most promising ones. Nevertheless, a MRI scan performed few days after infarction assesses a rapidly changing myocardium. In particular the infarct border zone that is believed to be a substrate for malignant arrhythmias, may change considerably during subsequent remodeling. Methods We analyzed 165 patients with AMI and primary angioplasty who underwent contrast enhanced MRI imaging both early (4 days in median) and late (6 months in median) after the acute event. MRI scar size was measured 15 minutes after gadolinium injection. Infarct border zone was defined as area with signal intensity between 3 and 6 standard deviations above healthy myocardium, infarct core as signal intensity above 6 standard deviations above healthy myocardium. Results Four days after infarction, MVO was present in 70 patients (42%) with a median size of 2.1 ml (IQR 0.95.2ml). After 6 months MVO was still present in 10 patients (6%) with a median size of 0.7 ml (IQR 0.51.6 ml). Infarct border zone was significantly smaller after 6 months (median 7.2 ml, IQR 4.0-10.2ml), when compared with the scan after 4 days (median 8.9 ml, IQR 5.9-14.9ml, p<0.001), while the size of infarct core zone did not change significantly (median 7.4 ml after 6 month, IQR 2.9-15.0, compared to 6.9 ml after 4 days, IQR 2.5-15.9, p=0.33). Conclusions MVO is still present after 6 months in a small fraction of patients. Contrary to the infarct core zone, the infarct border zone shrinks significantly during remodeling after acute myocardial infarction. Whether these changes have prognostic implications has to be tested on a larger patient population.

ObjectivesBecause the distribution volume and mechanism of extracellular and intravascular MR contrast media differ considerably, the enhancement pattern of chronic myocardial infarction with extracellular or intravascular media might also be different. This study aims to investigate the differences in MR enhancement patterns of chronic myocardial infarction between extracellular and intravascular contrast media.Materials and MethodsTwenty pigs with myocardial infarction underwent cine MRI, first pass perfusion MRI and delayed enhancement MRI with extracellular or intravascular media at four weeks after coronary occlusion. Myocardial blood flow (MBF) was determined with microsphere measurement. The infarction histopathological changes were evaluated by hematoxylin and eosin staining and Masson's trichrome method.ResultsCine MRI revealed the reduced wall thickening in chronic infarction compared with normal myocardium. Moreover, significant wall thinning in chronic infarction was observed in cine MRI. Peak first-pass signal intensity didn’t significantly differ between chronic infarction and normal myocardium no matter what kinds of contrast media. At the following delayed enhancement phase, extracellular media-enhanced signal intensity was significantly higher in chronic infarction than in normal myocardium. Conversely, intravascular media-enhanced signal intensity was almost equivalent among chronic infarction and normal myocardium. At four weeks after infarction, MBF in chronic infarction approached to that in normal myocardium. Large thick-walled vessels were detected at peri-infarction zones. The cardiomyocytes were replaced by scar tissue consisting of dilated blood vessels and discrete fibers of collagen.ConclusionsChronic infarction was characterized by the significantly reduced wall thickening and the definite wall thinning. First-pass myocardial perfusion defect was not detected in chronic infarction with two media due to the significantly recovered MBF and well-developed collateral vessels. Infarction remodeling enlarged the extracellular compartment, which was available for extracellular media but not accessible to intravascular media. Extracellular media identified chronic infarction as the hyper-enhancement; nonetheless, intravascular media didn’t provide delayed enhancement.

Cardiac Cell Therapy Fails to Rejuvenate the Chronically Scarred Rodent Heart.

CA-534-01 PULSED FIELD ABLATION COMPARED TO RADIOFREQUENCY ABLATION OF LEFT VENTRICULAR MYOCARDIUM IN A SWINE INFARCT MODEL

Introduction: Myocardial infarction (MI) survivors are at increased risk for ventricular arrhythmias and sudden death; risk directly correlates with infarct size and scar heterogeneity. The regenerative effects of cardiosphere-derived cells (CDCs),which are now in phase 2 clinical trials, are mediated by exosomes (CDC exo ).Like CDCs, CDC exo reduce scar size and increase viable mass in chronic MI. These naturally secreted nanoparticles mediate cell-cell signaling by transfer of bioactive payloads including microRNAs. Hypothesis: We hypothesized that post-MI hearts treated with CDC exo exhibit reduced inducibility of ventricular tachycardia (VT). Methods: An angioplasty balloon was inflated in the left anterior descending coronary artery for 150 minutes followed by one month of reperfusion in 7 female Yucatán minipigs. Electroanatomical mapping (EAM) was then performed to define the MI border zone (4.1-7mV NOGA tip potentials), after which we injected either CDC exo (7.5mg/1 ml n=4) or phosphate-buffered saline(PBS, 1ml, n=3), in 12-15 border zone sites via MYOSTAR catheter. Four weeks later, EAM was repeated and arrhythmia susceptibility was probed using both programmed ventricular stimulation and burst pacing (train of 8 beats from 400 to 200ms in 10 ms decrements) at the infarct border zone, and in healthy tissue near the posterolateral wall (&gt;10mv). Arrhythmia morphology was characterized by 12 lead ECG. Final infarct size was quantified by histology (TTC). Results: In CDC exo -injected pigs, infarct size was lower (11.4% vs 7.8%, p=0.05) and viable mass was higher (69.3g vs 79.3g, p=0.03) than in PBS controls. No sustained VT was induced by programmed ventricular stimulation. Burst pacing elicited VT which rapidly degenerated into ventricular fibrillation in all control animals (n=3), but in only 1 of 4 CDC exo -treated animals (p=0.04),when paced at both the infarct border and healthy myocardium. Conclusions: Exosomes from CDCs regenerate myocardium post-MI. Pigs treated with CDC exo exhibit reduced inducibility of sustained ventricular arrhythmias by burst pacing. This first demonstration of an anti-arrhythmic effect of exosomes motivates more extensive investigation of the effects of these nanoparticles on rhythm disorders.

The left and right ventricles of the human heart differ in embryology, shape, thickness, and function. Ventricular dyssynchrony often occurs in cases of heart failure. Our objectives were to assess whether differences in contractile properties exist between the left and right ventricles and to evaluate signs of left/right ventricular mechanical synchrony in isolated healthy and diseased human myocardium. Myocardial left and right ventricular trabeculae were dissected from nonfailing and end-stage failing human hearts. Baseline contractile force and contraction/relaxation kinetics of the left ventricle were compared to those of the right ventricle in the nonfailing group (n=41) and in the failing group (n=29). Correlation analysis was performed to assess the mechanical synchrony between left and right ventricular myocardium isolated from the same heart, in nonfailing (n=41) and failing hearts (n=29). The failing right ventricular myocardium showed significantly higher developed force (Fdev; P=0.001; d=0.98), prolonged time to peak (P<0.001; d=1.14), and higher rate of force development (P=0.002; d=0.89) and force decline (P=0.003; d=0.82) compared to corresponding left ventricular myocardium. In healthy myocardium, a strong positive relationship was present between the left and right ventricles in time to peak (r=0.58, P<0.001) and maximal kinetic rate of contraction (r=0.63, P<0.001). These coefficients were much weaker, often nearly absent, in failing myocardium. At the level of isolated cardiac trabeculae, contractile performance, specifically of contractile kinetics, is correlated in the nonfailing myocardium between the left and right ventricles' but this correlation is significantly weaker, or even absent, in end-stage heart failure, suggesting an interventricular mechanical dyssynchrony.

A catheter-based left ventricular (LV) endocardial mapping procedure using electromagnetic field energy for positioning of the catheter tip was designed to acquire simultaneous measurements of endocardial voltage potentials and myocardial contractility. We investigated such a mapping system to distinguish between infarcted and normal myocardium in an animal infarction model and in patients with coronary artery disease. Measurements of LV endocardial unipolar (UP) and bipolar (BP) voltages and local endocardial shortening were derived from dogs at baseline (n=12), at 24 hours (n=6), and at 3 weeks (n=6) after occlusion of the left anterior descending coronary artery. Also, 12 patients with prior myocardial infarction (MI) and 12 control patients underwent the LV endocardial mapping study for assessment of electromechanical function in infarcted versus healthy myocardial regions. In the canine model, a significant decrease in voltage potentials was noted in the MI zone at 24 hours (UP, 42. 8+/-9.6 to 29.1+/-12.2 mV, P=0.007; BP, 11.6+/-2.3 to 4.9+/-1.2 mV, P<0.0001) and at 3 weeks (UP, 41.0+/-8.9 to 13.9+/-3.9 mV, P<0.0001; BP, 11.2+/-2.8 to 2.4+/-0.4 mV, P<0.0001). No change in voltage was noted in zones remote from MI. In patients with prior MI, the average voltage was 7.2+/-2.7 mV (UP)/1.4+/-0.7 mV (BP) in MI regions, 17.8+/-4.6 mV (UP)/4.5+/-1.1 mV (BP) in healthy zones remote from MI, and 19.7+/-4.4 mV (UP)/5.8+/-1.0 mV (BP) in control patients without prior MI (P<0.001 for MI values versus remote zones or control patients). In the canine model and patients, local endocardial shortening was significantly impaired in MI zones compared with controls. These preliminary data suggest that infarcted myocardium could be accurately diagnosed and distinguished from healthy myocardium by a reduction in both electrical voltage and mechanical activity. Such a diagnostic electromechanical mapping study might be clinically useful for accurate assessment of myocardial function and viability.