Dynamics of High-Density Unipolar Epicardial Electrograms During PFA.

BACKGROUND: Pulsed field ablation (PFA) is a novel nonthermal cardiac ablation technology based on irreversible electroporation (IRE). While areas of IRE lead to durable lesions, the surrounding regions, where reversible electroporation occurs, recover. The behavior of local electrograms in areas of different electroporation levels remains unknown. The goal of this study is to characterize electrogram dynamics after PFA in IRE and reversible electroporation areas. METHODS: A total of 6 domestic swine were used. PFA was applied in the epicardium of the right and left ventricles using a focal monopolar catheter. Additional radiofrequency ablations were performed. Epicardial unipolar electrograms were acquired at baseline and for 60 minutes post PFA/radiofrequency ablation using a high-density electrode matrix attached to the epicardium. Electrogram dynamics were analyzed in areas corresponding to different levels of electroporation. Acute lesion formation was assessed after 3 to 5 hours by triphenyl tetrazolium chloride staining. RESULTS: Electrogram analysis demonstrated a clear association between electrogram changes and the level of electroporation. Immediately after PFA, electrograms displayed the following: a significant decrease in R/S-wave amplitude; a large elevation of the ST-segment; and a large decrease in their |(dV/dt)|max. Marked changes in electrograms were observed beyond the lesion area. Thereafter, a gradual recovery was observed. The evolution of all the electrogram parameters throughout the 60 minutes after PFA was significantly different (P<0.05) between the IRE and reversible electroporation areas. Acute lesion staining showed significantly larger depth for PFA lesions compared with radiofrequency ablation. CONCLUSIONS: This study shows that unipolar electrograms can differentiate between reversible electroporation and IRE areas during the first 30 minutes post ablation. Differences after the first 30 minutes are less evident. Our findings could result useful for immediate lesion assessment after PFA and warrant further investigation.

Parametric Study of Pulsed Field Ablation With Biphasic Waveforms in an In Vivo Heart Model: The Role of Frequency.

BACKGROUND: Pulsed field ablation (PFA) is a novel nonthermal cardiac ablation technology based on irreversible electroporation. Unfortunately, the characteristics of the electric field waveforms used in clinical and experimental PFA are not typically reported. This study examines the effect of the frequency of biphasic waveforms and compares biphasic to monophasic waveforms. METHODS: A total of 29 Sprague-Dawley rats were treated with PFA using an epicardial monopolar electrode. Biphasic waveforms with three different frequencies, 90, 260, and 450 kHz (10 bursts of 100 µs duration at 500 V or 800 V) and monophasic waveforms (10 pulses of 100 µs duration at 500 V) were studied. Collateral neuromuscular stimulation and temperature increase in the point of application were directly measured. Lesion formation was assessed 3 weeks after treatment by histopathologic analysis. Computer simulations were used to estimate the electric field lethal threshold for each condition. A previous in vitro study was performed to draw a complete characterization of the studied dependencies. RESULTS: Morphometric analysis demonstrated a significant association between chronic lesion size and waveform characteristics. For the same voltage level, monophasic waveforms yielded the largest lesions compared with any of the biphasic protocols (P<0.05). Increasing PFA frequency was associated with reduced neuromuscular stimulation but also with reduced ablation efficacy. Maximum absolute temperature increase recorded along a complete treatment was 3 °C. Vascular structures inside the lesions were preserved for all conditions. Computer simulation-based analysis showed that waveform frequency had a graded effect on the lethal electric field threshold, with threshold of 600 V/cm for monophasic waveforms versus 2000 V/cm for biphasic waveforms with a frequency of 450 kHz. CONCLUSIONS: Frequency is a major determinant of efficacy in biphasic PFA. Our results highlight the critical need of disclosing waveform characteristics when reporting the results of different PFA systems.

Electrophysiological and histological characterization of atrial scarring in a model of isolated atrial myocardial infarction.

Background: Characterization of atrial myocardial infarction is hampered by the frequent concurrence of ventricular infarction. Theoretically, atrial infarct scarring could be recognized by multifrequency tissue impedance, like in ventricular infarction, but this remains to be proven. Objective: This study aimed at developing a model of atrial infarction to assess the potential of multifrequency impedance to recognize areas of atrial infarct scar. Methods: Seven anesthetized pigs were submitted to transcatheter occlusion of atrial coronary branches arising from the left coronary circumflex artery. Six weeks later the animals were anesthetized and underwent atrial voltage mapping and multifrequency impedance recordings. The hearts were thereafter extracted for anatomopathological study. Two additional pigs not submitted to atrial branch occlusion were used as controls. Results: Selective occlusion of the atrial branches induced areas of healed infarction in the left atrium in 6 of the 7 cases. Endocardial mapping of the left atrium showed reduced multi-frequency impedance (Phase angle at 307 kHz: from -17.1° ± 5.0° to -8.9° ± 2.6°, p < .01) and low-voltage of bipolar electrograms (.2 ± 0.1 mV vs. 1.9 ± 1.5 mV vs., p < .01) in areas affected by the infarction. Data variability of the impedance phase angle was lower than that of bipolar voltage (coefficient of variability of phase angle at307 kHz vs. bipolar voltage: .30 vs. .77). Histological analysis excluded the presence of ventricular infarction. Conclusion: Selective occlusion of atrial coronary branches permits to set up a model of selective atrial infarction. Atrial multifrequency impedance mapping allowed recognition of atrial infarct scarring with lesser data variability than local bipolar voltage mapping. Our model may have potential applicability on the study of atrial arrhythmia mechanisms.

Phase angle by electrical bioimpedance is a predictive factor of hospitalisation, falls and mortality in patients with cirrhosis.

The phase angle is a versatile measurement to assess body composition, frailty and prognosis in patients with chronic diseases. In cirrhosis, patients often present alterations in body composition that are related to adverse outcomes. The phase angle could be useful to evaluate prognosis in these patients, but data are scarce. The aim was to analyse the prognostic value of the phase angle to predict clinically relevant events such as hospitalisation, falls, and mortality in patients with cirrhosis. Outpatients with cirrhosis were consecutively included and the phase angle was determined by electrical bioimpedance. Patients were prospectively followed to determine the incidence of hospitalisations, falls, and mortality. One hundred patients were included. Patients with phase angle ≤ 4.6° (n = 31) showed a higher probability of hospitalisation (35% vs 11%, p = 0.003), falls (41% vs 11%, p = 0.001) and mortality (26% vs 3%, p = 0.001) at 2-year follow-up than patients with PA > 4.6° (n = 69). In the multivariable analysis, the phase angle and MELD-Na were independent predictive factors of hospitalisation and mortality. Phase angle was the only predictive factor for falls. In conclusion, the phase angle showed to be a predictive marker for hospitalisation, falls, and mortality in outpatients with cirrhosis.

Changes in Local Atrial Electrograms and Surface ECG Induced by Acute Atrial Myocardial Infarction.

BACKGROUND: Atrial coronary branch occlusion is a hardly recognizable clinical entity that can promote atrial fibrillation. The low diagnostic accuracy of the ECG could deal with the characteristics of the ischemia-induced changes in local atrial electrograms, but these have not been described. OBJECTIVES: We analyzed the effects of selective acute atrial branch occlusion on local myocardial structure, atrial electrograms, and surface ECG in an experimental model close to human cardiac anatomy and electrophysiology. METHODS: Six anesthetized open-chest anesthetized pigs underwent surgical occlusion of an atrial coronary branch arising from the right coronary artery during 4 h. Atrial electrograms and ECG were simultaneously recorded. One additional pig acted as sham control. In all cases, the hearts were processed for anatomopathological analysis. RESULTS: Atrial branch occlusion induced patchy atrial necrosis with sharp border zone. During the first 30 min of occlusion, atrial electrograms showed progressive R wave enlargement (1.8 ± 0.6 mV vs. 2.5 ± 1.1 mV, p < 0.01), delayed local activation times (28.5 ± 8.9 ms vs. 36.1 ± 16.4 ms, p < 0.01), ST segment elevation (-0.3 ± 0.3 mV vs. 1.0 ± 1.0 mV, p < 0.01), and presence of monophasic potentials. Atrial ST segment elevation decreased after 2 h of occlusion. The electrical border zone was ∼1 mm and expanded over time. After 2 h of occlusion, the ECG showed a decrease in P wave amplitude (from 0.09 ± 0.04 mV to 0.05 ± 0.04 mV after 165 min occlusion, p < 0.05) and duration (64.4 ± 8.0 ms vs. 80.9 ± 12.6 ms, p < 0.01). CONCLUSION: Selective atrial branch occlusion induces patchy atrial infarction and characteristic changes in atrial activation, R/S wave, and ST segment that are not discernible at the ECG. Only indirect changes in P wave amplitude and duration were appreciated in advanced stages of acute coronary occlusion.

Influence of Left Bundle Branch Block on the Electrocardiographic Changes Induced by Acute Coronary Artery Occlusion of Distinct Location and Duration.

Background: Electrocardiographic (ECG) diagnosis of acute myocardial ischemia is hampered in the presence of left bundle branch block (LBBB). Objectives: We analyzed the influence of location and duration of myocardial ischemia on the ECG changes in pigs with LBBB. Methods: LBBB was acutely induced in 14 closed chest anesthetized pigs by local electrical ablation. Thereafter, episodes of 5 min catheter balloon occlusion followed by 10 min reperfusion of the left anterior descending (LAD), left circumflex (LCX), and right (RCA) coronary arteries were done sequentially in 5 pigs. Additionally, a 3-h occlusion of these arteries was performed separately in the other 9 pigs. A 15-lead ECG including leads V7 to V9 was continuously recorded. Results: Ablation induced LBBB showed QRS widening, loss of r wave in V1, and predominant R waves in V2 to V9. After 5 min of ischemia the occluded artery could be identified in all cases: the LAD by R waves and ST elevation in V1-V3; the LCX by both ST segment elevation in II, III, aVF, V7 to V9 and ST segment depression in V1 to V4; and the RCA by ST depression and new S-waves in all precordial leads. Three hours after coronary occlusion, ST segment changes declined progressively and only the LAD occlusion could be reliably recognized. Conclusion: LBBB did not mask the ECG recognition of the occluded coronary artery during the first 60 min of ischemia, but 3 h later only the LAD occlusion could be reliably identified. ST elevation in leads V7 to V9 is specific of LCX occlusion and it could be useful in the diagnosis of acute myocardial ischemia in the presence of LBBB.

Identification of new biophysical markers for pathological ventricular remodelling in tachycardia-induced dilated cardiomyopathy.

Our aim was to identify biophysical biomarkers of ventricular remodelling in tachycardia-induced dilated cardiomyopathy (DCM). Our study includes healthy controls (N = 7) and DCM pigs (N = 10). Molecular analysis showed global myocardial metabolic abnormalities, some of them related to myocardial hibernation in failing hearts, supporting the translationality of our model to study cardiac remodelling in dilated cardiomyopathy. Histological analysis showed unorganized and agglomerated collagen accumulation in the dilated ventricles and a higher percentage of fibrosis in the right (RV) than in the left (LV) ventricle (P = .016). The Fourier Transform Infrared Spectroscopy (FTIR) 1st and 2nd indicators, which are markers of the myofiber/collagen ratio, were reduced in dilated hearts, with the 1st indicator reduced by 45% and 53% in the RV and LV, respectively, and the 2nd indicator reduced by 25% in the RV. The 3rd FTIR indicator, a marker of the carbohydrate/lipid ratio, was up-regulated in the right and left dilated ventricles but to a greater extent in the RV (2.60-fold vs 1.61-fold, P = .049). Differential scanning calorimetry (DSC) showed a depression of the freezable water melting point in DCM ventricles - indicating structural changes in the tissue architecture - and lower protein stability. Our results suggest that the 1st, 2nd and 3rd FTIR indicators are useful markers of cardiac remodelling. Moreover, the 2nd and 3rd FITR indicators, which are altered to a greater extent in the right ventricle, are associated with greater fibrosis.

Summation and Cancellation Effects on QRS and ST-Segment Changes Induced by Simultaneous Regional Myocardial Ischemia.

Simultaneous ischemia in two myocardial regions is a potentially lethal clinical condition often unrecognized whose corresponding electrocardiographic (ECG) patterns have not yet been characterized. Thus, this study aimed to determine the QRS complex and ST-segment changes induced by concurrent ischemia in different myocardial regions elicited by combined double occlusion of the three main coronary arteries. For this purpose, 12 swine were randomized to combination of 5-min single and double coronary artery occlusion: Group 1: left Circumflex (LCX) and right (RCA) coronary arteries (n = 4); Group 2: left anterior descending artery (LAD) and LCX (n = 4) and; Group 3: LAD and RCA (n = 4). QRS duration and ST-segment displacement were measured in 15-lead ECG. As compared with single occlusion, double LCX+RCA blockade induced significant QRS widening of about 40 ms in nearly all ECG leads and magnification of the ST-segment depression in leads V1-V3 (maximal 228% in lead V3, p < 0.05). In contrast, LAD+LCX or LAD+RCA did not induce significant QRS widening and markedly attenuated the ST-segment elevation in precordial leads (maximal attenuation of 60% in lead V3 in LAD+LCX and 86% in lead V5 in LAD+RCA, p < 0.05). ST-segment elevation in leads V7-V9 was a specific sign of single LCX occlusion. In conclusion, concurrent infero-lateral ischemia was associated with a marked summation effect of the ECG changes previously elicited by each single ischemic region. By contrast, a cancellation effect on ST-segment changes with no QRS widening was observed when the left anterior descending artery was involved.

Comparison between endocardial and epicardial cardiac resynchronization in an experimental model of non-ischaemic cardiomyopathy.

Aims: Pacing from the left ventricular (LV) endocardium might increase the likelihood of response to cardiac resynchronization therapy. However, experimental and clinical data supporting this assumption are limited and controversial. The aim of this study was to compare the acute response of biventricular pacing from the LV epicardium and endocardium in a swine non-ischaemic cardiomyopathy (NICM) model of dyssynchrony. Methods and results: A NICM was induced in six swine by 3 weeks of rapid ventricular pacing. Biventricular stimulation was performed from 16 paired locations in the LV (8 epicardial and 8 endocardial) with two different atrioventricular (80 and 110 ms) intervals and three interventricular (0, +30, -30 ms) delays. The acute response of the aortic blood flow, LV and right ventricular (RV) pressures, LVdP/dtmax and LVdP/dtmin and QRS complex width and QT duration induced by biventricular stimulation were analysed. The haemodynamic and electrical beneficial responses to either LV endocardial or epicardial biventricular pacing were similar (ΔLVdP/dtmax: +7.8 ± 2.2% ENDO vs. +7.3 ± 1.5% EPI, and ΔQRS width: -16.8 ± 1.3% ENDO vs. -17.1 ± 1.9% EPI; P = ns). Pacing from LV basal regions either from the epicardium or endocardium produced better haemodynamic responses as compared with mid or apical LV regions (P < 0.05). The LV regions producing the maximum QRS complex shortening did not correspond to those inducing the best haemodynamic responses (EPI: r2 = 0.013, P = ns; ENDO: r2 = 0.002, P = ns). Conclusion: Endocardial LV pacing induced similar haemodynamic changes than pacing from the epicardium. The response to endocardial LV pacing is region dependent as observed in epicardial pacing.

Endocardial infarct scar recognition by myocardial electrical impedance is not influenced by changes in cardiac activation sequence.

BACKGROUND: Measurement of myocardial electrical impedance can allow recognition of infarct scar and is theoretically not influenced by changes in cardiac activation sequence, but this is not known. OBJECTIVES: The objectives of this study were to evaluate the ability of endocardial electrical impedance measurements to recognize areas of infarct scar and to assess the stability of the impedance data under changes in cardiac activation sequence. METHODS: One-month-old myocardial infarction confirmed by cardiac magnetic resonance imaging was induced in 5 pigs submitted to coronary artery catheter balloon occlusion. Electroanatomic data and local electrical impedance (magnitude, phase angle, and amplitude of the systolic-diastolic impedance curve) were recorded at multiple endocardial sites in sinus rhythm and during right ventricular pacing. By merging the cardiac magnetic resonance and electroanatomic data, we classified each impedance measurement site either as healthy (bipolar amplitude ≥1.5 mV and maximum pixel intensity <40%) or scar (bipolar amplitude <1.5 mV and maximum pixel intensity ≥40%). RESULTS: A total of 137 endocardial sites were studied. Compared to healthy tissue, areas of infarct scar showed 37.4% reduction in impedance magnitude (P < .001) and 21.5% decrease in phase angle (P < .001). The best predictive ability to detect infarct scar was achieved by the combination of the 4 impedance parameters (area under the receiver operating characteristic curve 0.96; 95% confidence interval 0.92-1.00). In contrast to voltage mapping, right ventricular pacing did not significantly modify the impedance data. CONCLUSION: Endocardial catheter measurement of electrical impedance can identify infarct scar regions, and in contrast to voltage mapping, the impedance data are not affected by changes in cardiac activation sequence.

Recognition of Fibrotic Infarct Density by the Pattern of Local Systolic-Diastolic Myocardial Electrical Impedance.

Myocardial electrical impedance is a biophysical property of the heart that is influenced by the intrinsic structural characteristics of the tissue. Therefore, the structural derangements elicited in a chronic myocardial infarction should cause specific changes in the local systolic-diastolic myocardial impedance, but this is not known. This study aimed to characterize the local changes of systolic-diastolic myocardial impedance in a healed myocardial infarction model. Six pigs were successfully submitted to 150 min of left anterior descending (LAD) coronary artery occlusion followed by reperfusion. 4 weeks later, myocardial impedance spectroscopy (1-1000 kHz) was measured at different infarction sites. The electrocardiogram, left ventricular (LV) pressure, LV dP/dt, and aortic blood flow (ABF) were also recorded. A total of 59 LV tissue samples were obtained and histopathological studies were performed to quantify the percentage of fibrosis. Samples were categorized as normal myocardium (<10% fibrosis), heterogeneous scar (10-50%) and dense scar (>50%). Resistivity of normal myocardium depicted phasic changes during the cardiac cycle and its amplitude markedly decreased in dense scar (18 ± 2 Ω·cm vs. 10 ± 1 Ω·cm, at 41 kHz; P < 0.001, respectively). The mean phasic resistivity decreased progressively from normal to heterogeneous and dense scar regions (285 ± 10 Ω·cm, 225 ± 25 Ω·cm, and 162 ± 6 Ω·cm, at 41 kHz; P < 0.001 respectively). Moreover, myocardial resistivity and phase angle correlated significantly with the degree of local fibrosis (resistivity: r = 0.86 at 1 kHz, P < 0.001; phase angle: r = 0.84 at 41 kHz, P < 0.001). Myocardial infarcted regions with greater fibrotic content show lower mean impedance values and more depressed systolic-diastolic dynamic impedance changes. In conclusion, this study reveals that differences in the degree of myocardial fibrosis can be detected in vivo by local measurement of phasic systolic-diastolic bioimpedance spectrum. Once this new bioimpedance method could be used via a catheter-based device, it would be of potential clinical applicability for the recognition of fibrotic tissue to guide the ablation of atrial or ventricular arrhythmias.

Early detection of acute transmural myocardial ischemia by the phasic systolic-diastolic changes of local tissue electrical impedance.

Myocardial electrical impedance is influenced by the mechanical activity of the heart. Therefore, the ischemia-induced mechanical dysfunction may cause specific changes in the systolic-diastolic pattern of myocardial impedance, but this is not known. This study aimed to analyze the phasic changes of myocardial resistivity in normal and ischemic conditions. Myocardial resistivity was measured continuously during the cardiac cycle using 26 different simultaneous excitation frequencies (1 kHz-1 MHz) in 7 anesthetized open-chest pigs. Animals were submitted to 30 min regional ischemia by acute left anterior descending coronary artery occlusion. The electrocardiogram, left ventricular (LV) pressure, LV dP/dt, and aortic blood flow were recorded simultaneously. Baseline myocardial resistivity depicted a phasic pattern during the cardiac cycle with higher values at the preejection period (4.19 ± 1.09% increase above the mean, P < 0.001) and lower values during relaxation phase (5.01 ± 0.85% below the mean, P < 0.001). Acute coronary occlusion induced two effects on the phasic resistivity curve: 1) a prompt (5 min ischemia) holosystolic resistivity rise leading to a bell-shaped waveform and to a reduction of the area under the LV pressure-impedance curve (1,427 ± 335 vs. 757 ± 266 Ω·cm·mmHg, P < 0.01, 41 kHz) and 2) a subsequent (5-10 min ischemia) progressive mean resistivity rise (325 ± 23 vs. 438 ± 37 Ω·cm at 30 min, P < 0.01, 1 kHz). The structural and mechanical myocardial dysfunction induced by acute coronary occlusion can be recognized by specific changes in the systolic-diastolic myocardial resistivity curve. Therefore these changes may become a new indicator (surrogate) of evolving acute myocardial ischemia.

Myocardial contractility assessed by dynamic electrical impedance measurements during dobutamine stress.

In this study, the electrical impedance of myocardial tissue is measured dynamically during the cardial cycle. The multisine-based approach used to perform electrical impedance spectroscopy (EIS) measurements allows acquiring complete spectral impedance information of the tissue dynamics during contraction. Measurements are performed in situ in the left ventricule of swines during contractility stress tests induced by dobutamine infusion. Additionally, the ECG and the left ventricular (LV) pressure are also acquired synchronously to the impedance signals. The calculated impedance magnitude exhibits a periodic behavior during tissue contraction. The amplitude (peak-to-peak) of this signal is quantified and the compared to the maximum first derivative of the LV pressure (dP/dtmax) that is used as an indicator of contractility variations. The results show a linear correlation between impedance amplitude and dP/dtmax during dobutamine-increased contractility. The present work demonstrates how fast EIS measurements during heart contraction can represent a feasible method to assess changes in myocardial contractility.