ORIGINAL RESEARCH published: 12 February 2019 doi: 10.3389/fphys.2019.00082 Influence of Left Bundle Branch Block on the Electrocardiographic Changes Induced by Acute Coronary Artery Occlusion of Distinct Location Edited by: and Duration Ruben Coronel, Esther Jorge † , Eduard Solé-González † , Gerard Amorós-Figueras, Dabit Arzamendi, University of Amsterdam, Netherlands Jose M. Guerra, Xavier Millán, Miquel Vives-Borrás and Juan Cinca* Reviewed by: Tobias Opthof, Department of Cardiology, Hospital de la Santa Creu i Sant Pau, Institute of Biomedical Research IIB Sant Pau, CIBERCV, Academic Medical Center (AMC), Universitat Autònoma de Barcelona, Barcelona, Spain Netherlands Alessandro Capucci, Polytechnical University of Marche, Background: Electrocardiographic (ECG) diagnosis of acute myocardial ischemia is Italy hampered in the presence of left bundle branch block (LBBB). Richard Leonard Verrier, Beth Israel Deaconess Medical Objectives: We analyzed the influence of location and duration of myocardial ischemia Center and Harvard Medical School, on the ECG changes in pigs with LBBB. United States *Correspondence: Methods: LBBB was acutely induced in 14 closed chest anesthetized pigs by local Juan Cinca electrical ablation. Thereafter, episodes of 5 min catheter balloon occlusion followed by jcinca@santpau.cat † These 10 min reperfusion of the left anterior descending (LAD), left circumflex (LCX), and right authors have contributed equally to this work (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 Specialty section: leads V7 to V9 was continuously recorded. This article was submitted to Cardiac Electrophysiology, Results: Ablation induced LBBB showed QRS widening, loss of r wave in V1, and a section of the journal Frontiers in Physiology predominant R waves in V2 to V9. After 5 min of ischemia the occluded artery could be Received: 25 October 2018 identified in all cases: the LAD by R waves and ST elevation in V1–V3; the LCX by both Accepted: 24 January 2019 ST segment elevation in II, III, aVF, V7 to V9 and ST segment depression in V1 to V4; Published: 12 February 2019 and the RCA by ST depression and new S-waves in all precordial leads. Three hours Citation: Jorge E, Solé-González E, after coronary occlusion, ST segment changes declined progressively and only the LAD Amorós-Figueras G, Arzamendi D, occlusion could be reliably recognized. Guerra JM, Millán X, Vives-Borrás M and Cinca J (2019) Influence of Left Conclusion: LBBB did not mask the ECG recognition of the occluded coronary artery Bundle Branch Block on during the first 60 min of ischemia, but 3 h later only the LAD occlusion could be reliably the Electrocardiographic Changes Induced by Acute Coronary Artery identified. ST elevation in leads V7 to V9 is specific of LCX occlusion and it could be Occlusion of Distinct Location useful in the diagnosis of acute myocardial ischemia in the presence of LBBB. and Duration. Front. Physiol. 10:82. doi: 10.3389/fphys.2019.00082 Keywords: myocardial ischemia, coronary occlusion, left bundle block, ECG, swine Frontiers in Physiology | www.frontiersin.org 1 February 2019 | Volume 10 | Article 82 Jorge et al. Ischemia and Left Bundle Block INTRODUCTION maintained analgesia. This study was carried out in accordance with the recommendations of the Guide for the Care and Use The diagnosis of acute myocardial infarction (AMI) in patients of Laboratory Animals, 8th ed. (National Research Council. with left bundle branch block (LBBB) is a clinical challenge Washington, DC: The National Academies Press, 2010). The because this condition may entail a high mortality (Col and protocol was approved by the Animal Ethics Committee of Weinberg, 1972; Hindman et al., 1978) and, moreover, a reliable our Institution. electrocardiographic (ECG) diagnosis is not often possible (Shlipak et al., 1999; Jain et al., 2011). The central feature limiting Experimental Procedures the diagnostic accuracy of the ECG in patients with AMI and Radiofrequency (RF) Ablation of the Left Bundle LBBB is the coexistence of QRS and ST segment abnormalities Branch primarily caused by the disturbed cardiac activation. In the Closed-chest blockade of the left bundle branch was performed absence of concurrent ischemia, the direction of the ST segment following a previously reported model in swine (Rigol et al., displacements (elevation or depression) secondary to LBBB are 2013). We catheterized the femoral artery and the femoral vein opposite to the polarity of the corresponding QRS complex using the Seldinger’s technique. Under fluoroscopic guidance, (Willems et al., 1985) and a certain degree of proportionality an ablation electrocatheter (7F Blazer, Boston Scientific ) was R between the magnitude of the ST segment deviation and the advanced to the left ventricle (LV) and then positioned just amplitude of the QRS complex can be found. below the aortic valve. A second electrocatheter was placed In the presence of acute myocardial ischemia, the newly at the apex of the right ventricle (RV) for pacing purposes. generated ST segment changes may still maintain the opposite The LV electrocatheter was connected to a Prucka System direction to the QRS complex polarity or, at the contrary, (Prucka Engineering, Inc., Houston, TX, United States) and both may turn into the same direction. The ECG algorithms was slightly moved in the septal region of the outflow commonly used to recognize an AMI in patients with LBBB tract to record the left bundle branch potential which was are mainly based on the relationship between ST segment/QRS recognized as a sharp spike preceding (<35 ms) the onset of polarity (Sgarbossa et al., 1996) and on the proportionality the endocardial ventricular potential (Figure 1A). The right between the ST segment/QRS amplitude (Smith et al., 2012). ventricular electrocatheter was connected to a temporary external These algorithms afforded a good diagnostic specificity but pacemaker (Medtronic Inc., Minneapolis, MN, United States) a reduced sensitivity (Tabas et al., 2008). However, they do and was programmed for regular ventricular pacing (V00) at not consider the location of the coronary occlusion or the 160 bpm. RF applications (30 W, 30 s) were delivered in the timing of the evolving ischemic event. It is not well known region of the left bundle potential until a LBBB pattern was to which extent the specific ECG patterns induced by a recorded in the ECG. Since pigs are prone to develop ventricular particular occluded artery are modified by the altered activation- fibrillation under application of RF current, we administered a repolarization sequences in hearts with LBBB. Likewise, the continuous intravenous perfusion of amiodarone (300 mg/h) and well-recognized spontaneous attenuation of the ST segment immediately before the application of RF ablation, we paced the changes during the course of the ischemic process (Janse RV at 160 bpm to homogenize the ventricular refractoriness. et al., 1979; Cinca et al., 1980) will predictably influence Once the LBBB was created, the RV electrocatheter was placed the ECG criteria for AMI in presence of LBBB, but this to the lateral wall of the right atrium to pace the heart at 105 bpm needs to be determined. throughout the study. This procedure was done to permit a better This study was designed to analyze the influence of the comparison of the ECG changes induced among the study pigs. location and duration of acute myocardial ischemia on the ECG The LBBB pattern was defined by the appearance of: (1) widening changes in hearts with LBBB. We used a closed-chest swine model of QRS complex associated with secondary ST segment and T of LBBB induced acutely by local radiofrequency current ablation wave changes; (2) QS pattern in lead V1; and (3) switch from of the specialized left conduction bundle. the baseline r/S complex pattern in left precordial leads to a predominant R wave pattern with absence of Q waves. MATERIALS AND METHODS Coronary Artery Occlusion Acute transmural myocardial ischemia was induced by Study Population percutaneous coronary catheter balloon occlusion. We This study was carried out on anesthetized, closed-chest, introduced a 6F guiding catheter (Cordis) into a femoral domestic swine (Landrace-Large White cross) weighing artery and it was advanced to the ostium of the left or the right 40 kg. The animals were premedicated with midazolam coronary arteries under fluoroscopic guidance Then, a 3 mm (0.6 mg/kg; 5 mg/ml) and ketamine (12 mg/kg; 100 mg/ml) diameter over-the-wire catheter balloon (Cordis) was placed at intramuscularly. General anesthesia was induced with the mid segment of one of the three main coronary arteries. intravenous propofol (2–4 mg/kg; 10 mg/ml) and was The appropriate position of the balloon was confirmed by maintained with a mixture of oxygen and sevoflurane inhalation coronary angiography. Anticoagulation was induced in all cases (2.5%–3.5%). After endotracheal intubation, the animals were by an intravenous bolus of unfractionated heparin (150 UI/kg) mechanically ventilated. Fentanyl (2.5 µg/kg; 0.05 mg/ml) followed by sequential boluses (100 UI/kg) hourly until the end was administered intravenously during the procedure for of the study. Frontiers in Physiology | www.frontiersin.org 2 February 2019 | Volume 10 | Article 82 Jorge et al. Ischemia and Left Bundle Block FIGURE 1 | Graphic illustration of the experimental model of left bundle branch block induced in 14 open chest anesthetized pigs. (A) From top to bottom shows (1) an angiographic frame depicting the position of the ablation electrocatheter (ABL) in the LV outflow tract close to the region of the left bundle branch region and the pacing electrocatheter in the apex of the right ventricle (RV), (2) endocardial bipolar electrograms from the ABL electrocatheter showing the left bundle potential (arrow), and (3) a macroscopic view of the subaortic LV endocardium showing the ablation lesion (white arrow) close to the left conduction system. (B) ECG recording in a pig before and after induction of LBBB. (C) Bars illustrate the mean values and whiskers the SEM of the QRS complex duration and R-S wave amplitude before and after induction of LBBB measured in all ECG leads in 14 pigs. ∗∗ p value < 0.01, ∗∗∗ p value < 0.001 LBBB vs. baseline. LBBB = Left bundle branch block. 15 Lead-Electrocardiogram (ECG) Protocol #1 A 15 lead-ECG was continuously recorded and stored on Attempted to compare the ECG changes induced by ischemia a CardioSoft ECG system (Version 6.7.3, GE Healthcare, in three different myocardial regions in the same animal. Each Freiburg, Germany). Due to the species anatomy, we placed the case was sequentially submitted to a 5-min occlusion followed conventional precordial leads V1-V6 one intercostal space above by 10 min of reperfusion of the mid segments of the left that used in current clinical electrocardiography (Noriega et al., anterior descending (LAD), left circumflex (LCX), and right 2013). The three additional posterior chest leads V7–V9 were coronary (RC) arteries. In all instances the ischemic ECG changes placed after lead V6 at regular interelectrode spaces. The ECG was recovered during the reperfusion period. To minimize the recorded at baseline, after induction of LBBB, and continuously preconditioning effect of repeated occlusions in the same heart, during the coronary occlusion sequences. In each ECG recording, we randomized the occlusion sequences among the study pigs. we measured the following parameters using electronic calipers (Cardio-Calipers software, Iconico©) and imaging magnification: Protocol #2 (1) QRS complex duration; (2) amplitude of the R wave and S Addressed to describe the effect of time on the ECG changes wave; and (3) ST segment displacement at the J point. along 3 hours of coronary occlusion analyzed separately in three different myocardial territories in pigs with LBBB. The animals were divided into three groups according to the Study Protocol occluded coronary artery: LAD, LCX, or RCA. In all cases To achieve the main objectives of the study we delineated two the ECG was continuously recorded during the coronary experimental protocols. occlusion sequences. Frontiers in Physiology | www.frontiersin.org 3 February 2019 | Volume 10 | Article 82 Jorge et al. Ischemia and Left Bundle Block At the end of the study the animals were euthanized with intravenous injection of potassium chloride. Data Analysis Quantitative data were expressed as the mean ± standard error of the mean (SEM). The changes in the ECG variables from baseline to LBBB induction were evaluated by the analysis of variance (ANOVA) with Bonferroni correction for post hoc comparisons. A p value < 0.05 was considered significant. All analysis were performed using SPSS v.22.0 (IBM SPSS Inc., Chicago, IL, United States). RESULTS Study Population An effective block of the left bundle was achieved in 22 out of 29 pigs (76% rate of success). The 22 pigs with LBBB were submitted to the two study protocols and 8 of them (4 in each protocol) died because of ventricular arrhythmias or AV block induced during the coronary occlusion sequences. Therefore, 14 pigs with LBBB completed the entire study (5 pigs in protocol #1 and 9 in protocol #2). All animals included in the study were free of significant atherosclerotic coronary artery disease. LBBB Pattern Induced by RF Ablation As illustrated in Figures 1A,B, application of RF current in the endocardial sites with recorded local left bundle branch FIGURE 2 | Representative ECG after 5 min of myocardial ischemia in one pig potentials, induced a LBBB pattern characterized by: (a) widening with left bundle branch block (LBBB) induced by electrical ablation. ECG changes induced by 5 min occlusion of the left anterior descending (LAD), left of the QRS complex associated with secondary ST segment circumflex (LCX), and right (RCA) coronary arteries in the same pig. changes, (b) disappearance of the r wave in lead V1, (c) abrupt appearance of predominant R waves in leads V2 to V9 contrasting with the pre-ablation rS complex seen in these leads, and (d) change in the QRS axis from a left deviation at baseline to an we did not find appreciable ST segment elevation in leads II, AQRS of about 60◦ . The quantitative changes in QRS complex III, or aVF. duration and R/S wave amplitude elicited by left bundle RF ablation in the 14 included pigs with LBBB pigs are illustrated Effects of Duration of Coronary in Figure 1C. Occlusion on the ECG Changes (Protocol #2) Effects of Location of Coronary Figures 4–6 summarize the time course of the ischemic ECG Occlusion on the ECG Changes changes during 180 min of coronary occlusion. As compared (Protocol #1) with the first 5 min of ischemia, the magnitude of the ST Series of 5 min occlusion–10 min reperfusion involving segment changes decreased progressively over time in the three sequentially the LAD, LCX, and RCA of the same subject were explored coronary territories. However, 180 min after coronary performed in 5 pigs with LBBB. Typical ECG tracings recorded occlusion the ST segment deviation still remained apparent in during the separate occlusion of the 3 coronary arteries are pigs with LAD occlusion (Figure 4), but underwent mostly presented in Figure 2 and the mean ECG changes for the entire unappreciable in cases with RCA (Figure 5) and especially in group are graphically represented in Figure 3. Occlusion of the those with LCX occlusion (Figure 6). The magnitude of the LAD induced: (a) Increased R waves with ST segment elevation R wave changes in leads V1–V2 in cases of LAD occlusion (monophasic potentials) in leads V1 to V3; and (b) slight also decreased over time. The trends of the R/S patterns in reciprocal ST segment depression in leads V7-V9. Occlusion of precordial leads remained comparable after 180 min of ischemia the LCX induced ST segment elevation in leads II, III, aVF, and in pigs with LCX and RCA occlusion. To comparatively analyze V6 to V9 with reciprocal ST segment depression in leads V1 the ECG changes in the three coronary territories at the same to V3. Occlusion of the RCA elicited ST segment depression scale, Supplementary Figure S1 illustrates the quantitative ST in all precordial leads (from V1 to V9) with decreased R wave segment changes and Supplementary Figure S2 typical 15-lead voltage and reappearance of S waves in these leads. In our model ECG patterns. Frontiers in Physiology | www.frontiersin.org 4 February 2019 | Volume 10 | Article 82 Jorge et al. Ischemia and Left Bundle Block FIGURE 3 | ECG changes induced by 5 min coronary occlusion in 5 pigs with left bundle branch block (LBBB) induced by electrical ablation. Bars represent the mean values and whiskers the SEM of the ST segment (upper panels), and R- S waves (lower panels) LBBB and after 5 min occlusion of the left anterior descending (LAD), left circumflex (LCX), and right (RCA) coronary arteries. DISCUSSION diagnostic accuracy of the ECG, several algorithms have been proposed but often they only afford a modest sensitivity and, Main Findings on the other hand, were not purposely designed to consider the In this study we have analyzed systematically the influence of location or the duration of the coronary occlusion (Sgarbossa the location and time duration of acute myocardial ischemia et al., 1996; Smith et al., 2012). on the ECG changes in pigs with LBBB. Our data revealed In the absence of intraventricular conduction defects, the site that within the first 5 min of ischemia, the ECG changes could of coronary occlusion is well recognized by the widely established identify the LAD, LCX and RCA occlusion. However, 3 h ECG criteria (Wagner et al., 2009; Noriega et al., 2014), but in the later, only involvement of the LAD was reliably recognizable. presence of LBBB the validity of these ECG patterns has not been In addition, our study highlighted the utility of the posterior fully confirmed. The delayed and heterogeneous activation of the thoracic leads V7 to V9 to differentiate occlusion of the LCX in LV in hearts with LBBB alters the normal cardiac repolarization the presence of LBBB. sequence and consequently, the mismatch between the spatial location of the acute ischemic region and the moment of its local repolarization would likely influence the ensuing ischemic Effects of Location and Duration of changes in QRS morphology and ST segment displacement. Acute Myocardial Ischemia Our study affords novel data on the potential influence Electrocardiographic diagnosis of acute coronary occlusion in (i.e., “masking effect”) of the LBBB on the ECG patterns patients presenting a concomitant LBBB is frequently uncertain. induced by separate acute occlusion of the LAD, LCX, and Indeed, studies in cases with acute chest pain and new or RCA in the same individual. Taking as a reference a previous presumably new LBBB submitted to primary percutaneous study in pigs not submitted to left bundle ablation (Vives- coronary intervention revealed that only 39% of cases had the Borrás et al., 2018), the present data showed that in the final diagnosis of AMI (Jain et al., 2011). To improve the very early stages of coronary occlusion the affected coronary Frontiers in Physiology | www.frontiersin.org 5 February 2019 | Volume 10 | Article 82 Jorge et al. Ischemia and Left Bundle Block FIGURE 4 | ECG changes induced by 180 min occlusion of the left anterior descending (LAD) coronary artery in 3 pigs with left bundle branch block (LBBB) induced by electrical ablation. Left panel: ECG recordings at 5, 60, 120, and 180 min of LAD occlusion in a pig with LBBB. Right panel: Bars illustrate the mean values and whiskers the SEM of the ST segment deviation at 5, 60, 120, and 180 min of LAD occlusion in 3 pigs with LBBB. segment depicts similar ECG patterns both in pigs with Study Limitations and without LBBB. The reliability of the swine model of LBBB used in this study is A constant characteristic of a permanent occlusion of a based on: (a) the abrupt increase in QRS complex duration and coronary artery is that the magnitude of the ischemic ST appearance of R waves with secondary ST segment changes in segment changes decline spontaneously over time due to a precordial leads, and (b) the development of an abnormal LV concurrent increase of the electrical tissue resistivity inside contraction pattern comparable to that observed in patients with the ischemic myocardial region (Kléber et al., 1987; Cinca LBBB as was described in a similar swine model (Rigol et al., et al., 1997). The progressive attenuation of the ST segment 2013). Moreover, the characteristic delay in the interventricular changes after 3 h of coronary occlusion was noticeable in septal activation found in patients with LBBB has been also our cases. At this stage only the LAD occlusion could be confirmed by LV electroanatomical mapping recordings in pigs reliably recognized since the ST segment changes in cases with ablation induced LBBB (Soto Iglesias et al., 2017). of LCX and RCA occlusion mostly returned to baseline The QRS duration both at baseline and after induction of levels within 3 h. LBBB in pigs is shorter than that observed in patients with Frontiers in Physiology | www.frontiersin.org 6 February 2019 | Volume 10 | Article 82 Jorge et al. Ischemia and Left Bundle Block FIGURE 5 | ECG changes induced by 180 min occlusion of the right (RCA) coronary artery in 3 pigs with left bundle branch block (LBBB) induced by electrical ablation. Left panel: ECG recordings at 5, 60, 120, and 180 min of RCA occlusion in a pig with LBBB. Right panel: Bars illustrate the mean values and whiskers the SEM of the ST segment deviation at 5, 60, 120, and 180 min of RCA occlusion in 3 pigs with LBBB. and without LBBB. This species difference would likely relay that acute ischemia in the LV inferior region secondary to on the distinct transmural distribution of their specialized acute RCA occlusion could evoke modest ST segment elevation conduction system. Thus, a more transmural penetration of in leads II, III, and aVF in pigs, as compared with humans. Purkinje distribution in pigs (Holland and Brooks, 1976) However, in both species the reciprocal ST segment depression allows a faster ventricular excitation and a rather simultaneous induced by occlusion of the RCA was remarkable in precordial epicardial and endocardial activation (Hamlin et al., 1975; Ideker leads V1 to V4. and Huang, 2005) as compared with a wider spread of the Even though we cannot entirely exclude a preconditioning endocardial to epicardial activation in men (Durrer et al., 1970; effect on the ST segment changes after repeated coronary Opthof et al., 2017). occlusions, we have observed noticeable ST segment changes In addition, the absence of progressively increasing R waves during the first five minutes of occlusion in each of the from lead V1 to V6 is a species characteristic of pigs could three coronary arteries explored. Moreover, the objective of be in part due to the vertical intrathoracic position of their the study was not establishing a quantitative comparison of heart. This particular intrathoracic position can also explain the ST segment changes among the three ischemic regions. To Frontiers in Physiology | www.frontiersin.org 7 February 2019 | Volume 10 | Article 82 Jorge et al. Ischemia and Left Bundle Block FIGURE 6 | ECG changes induced by 180 min occlusion of the left circumflex (LCX) coronary artery in 3 pigs with left bundle branch block (LBBB) induced by electrical ablation. Left panel: ECG recordings at 5, 60, 120, and 180 min of LCX occlusion in a pig with LBBB. Right panel: Bars illustrate the mean values and whiskers the SEM of the ST segment deviation at 5, 60, 120, and 180 min of LCX occlusion in 3 pigs with LBBB. minimize the preconditioning effect of repeated occlusions in as are the ECG patterns induced by selective occlusion of the the same heart, we randomized the occlusion sequences among LAD, LCX, or RCA in both species (Noriega et al., 2014; Vives- the study pigs. Borrás et al., 2018). Consequently, the present data suggest Although the incidence of multivessel disease in patients with that during the first 60 min of a coronary occlusion, the acute STEMI and LBBB is relatively high, clinical extrapolation location of the culprit vessel in patients with LBBB could be of our results may be supported by the fact that in a previous predicted by the classical electrocardiographic patterns described study (Noriega et al., 2014) we found that patients with STEMI in patients free of conduction disturbances. By contrast, 3 h with single or multivessel coronary disease have concordant later only the occlusion of the LAD would remain identifiable artery-related ST-segment patterns. by the ECG. A matter of debate in patients with ST segment elevation Clinical Implications myocardial infarction (STEMI) and LBBB is whether the clinical Extrapolation of the electrocardiographic findings of our study to management should be approached differently if the conduction medical practice is tenable because the coronary distribution and block had appeared acutely in the context of the AMI, or cellular electrophysiologic derangements caused by myocardial anteceded the ischemic event. The current guidelines recommend ischemia in pigs are similar to humans (Cinca et al., 1980), a similar emergent reperfusion referral policy independently of Frontiers in Physiology | www.frontiersin.org 8 February 2019 | Volume 10 | Article 82 Jorge et al. Ischemia and Left Bundle Block the time of presentation of the LBBB (Ibanez et al., 2018). Our LBBB will not impede to diagnose an ischemic event or to localize data will support this recommendation but mainly in patients the culprit coronary artery guided by the ECG changes. By attended 60 min beyond the onset of chest pain because in earlier contrast, 3 h later, only occlusion of the LAD will be identifiable. stages of ischemia, the masking effect of a preexisting LBBB on Prospective clinical studies considering the location and duration the ECG changes might be negligible. Furthermore, if the LBBB of the ischemia are needed to confirm the present hypothesis had appeared acutely in the course of the ischemic process, then aimed at improving the guideline’s recommendations. the masking influence on the ECG changes would be even less notorious because the ischemic LBBB is often associated with large infarcts and these are expected to induce overt acute ST AUTHOR CONTRIBUTIONS segment and QRS changes. A practical recommendation derived from our study is the JC conceived and design of the research. EJ, ES-G, GA-F, DA, pertinence to routinely record the posterior thoracic leads V7 to JG, XM, MV-B, and JC performed the experiments, edited V9 in patients with acute coronary syndromes based on the high and revised manuscript, and approved the final version of diagnostic yielding of these leads in cases of LCX occlusion. In a the manuscript. EJ, ES-G, GA-F, and JC analyzed data and series of patients with LCX occlusion (Vives-Borrás et al., 2017) interpreted results of experiments, prepared the figures and we have found that leads V7 to V9 depict ST segment elevation drafted the manuscript. even in cases showing only a ST segment depression pattern in the whole ECG. In the swine model we have also confirmed that in contrast to LAD or RCA, the LCX occlusion was the only FUNDING one depicting ST segment elevation in leads V6 to V9 (Vives- Borrás et al., 2018). The present study extends this observation to This work was supported by Spanish Ministerio de Economia pigs with LBBB, thus giving foundation to further clinical studies y Competitividad, Instituto de Salud Carlos III, Centro de analyzing the validity of this sign to diagnose LCX occlusion in Investigación Biomédica en Red Enfermedades Cardiovaculares, patients with LBBB. CIBERCV (CB16/11/00276), and Fondo Europeo de Desarrollo Regional (FEDER). CONCLUSION SUPPLEMENTARY MATERIAL By handling a swine model of ablation induced LBBB our data The Supplementary Material for this article can be found support the hypothesis that in patients attended during the first online at: https://www.frontiersin.org/articles/10.3389/fphys. 60 min of acute coronary occlusion, the presence of a preexisiting 2019.00082/full#supplementary-material REFERENCES Holland, R. P., and Brooks, H. (1976). The QRS complex during myocardial ischemia. An experimental analysis in the porcine heart. J. Clin. Invest. 57, Cinca, J., Janse, M. J., Moréna, H., Candell, J., Valle, V., and Durrer, D. (1980). 541–550. doi: 10.1172/JCI108309 Mechanism and time course of the early electrical changes during acute Ibanez, B., James, S., Agewall, S., Antunes, M. J., Bucciarelli-Ducci, C., Bueno, H., coronary artery occlusion. An attempt to correlate the early ECG changes et al. (2018). 2017 ESC Guidelines for the management of acute myocardial in man to the cellular electrophysiology in the pig. Chest 77, 499–505. doi: infarction in patients presenting with ST-segment elevation: the Task Force for 10.1378/chest.77.4.499 the management of acute myocardial infarction in patients presenting with ST- Cinca, J., Warren, M., Carreño, A., Tresànchez, M., Armadans, L., segment elevation of the European Society of Cardiology (ESC). Eur. Heart J. Gómez, P., et al. (1997). Changes in myocardial electrical impedance 39, 119–177. doi: 10.1093/eurheartj/ehx393 induced by coronary artery occlusion in pigs with and without Ideker, R. E., and Huang, J. (2005). Our search for the porcine mother rotor. Ann. preconditioning: correlation with local ST-segment potential and Noninvasive Electrocardiol. 10, 7–15. doi: 10.1111/j.1542-474X.2005.00071.x ventricular arrhythmias. Circulation 96, 3079–3086. doi: 10.1161/01.CIR.96. Jain, S., Ting, H. T., Bell, M., Bjerke, C. M., Lennon, R. J., Gersh, B. J., et al. (2011). 9.3079 Utility of left bundle branch block as a diagnostic criterion for acute myocardial Col, J. J., and Weinberg, S. L. (1972). The incidence and mortality of infarction. Am. J. Cardiol. 107, 1111–1116. doi: 10.1016/j.amjcard.2010.12.007 intraventricular conduction defects in acute myocardial infarction. Janse, M. J., Cinca, J., Moréna, H., Fiolet, J. W., Kléber, A. G., de Vries, G. P., Am. J. Cardiol. 29, 344–350. doi: 10.1016/0002-9149(72)90 et al. (1979). The " border zone" in myocardial ischemia. An 529-2 electrophysiological, metabolic, and histochemical correlation in the pig heart. Durrer, D., van Dam, R. T., Freud, G. E., Janse, M. J., Meijler, F. L., and Arzbaecher, Circ. Res. 44, 576–588. doi: 10.1161/01.RES.44.4.576 R. C. (1970). Total excitation of the isolated human heart. Circulation 41, Kléber, A. G., Riegger, C. B., and Janse, M. J. (1987). Electrical uncoupling and 899–912. doi: 10.1161/01.CIR.41.6.899 increase of extracellular resistance after induction of ischemia in isolated, Hamlin, R. L., Burton, R. R., Leverett, S. D., and Burns, J. W. (1975). Ventricular arterially perfused rabbit papillary muscle. Circ. Res. 61, 271–279. doi: 10.1161/ activation process in minipigs. J. Electrocardiol. 8, 113–116. doi: 10.1016/S0022- 01.RES.61.2.271 0736(75)80018-5 Noriega, F. J., Jorge, E., Arzamendi, D., and Cinca, J. (2013). Mechanism and Hindman, M. C., Wagner, G. S., JaRo, M., Atkins, J. M., Scheinman, M. M., diagnostic potential of reciprocal ECG changes induced by acute coronary DeSanctis, R. W., et al. (1978). The clinical significance of bundle branch block artery occlusion in pigs. Heart Rhythm 10, 883–890. doi: 10.1016/j.hrthm.2013. complicating acute myocardial infarction. 1. Clinical characteristics, hospital 02.022 mortality, and one-year follow-up. Circulation 58, 679–688. doi: 10.1161/01. Noriega, F. J., Vives-Borrás, M., Solé-González, E., García-Picart, J., Arzamendi, D., CIR.58.4.679 and Cinca, J. (2014). Influence of the extent of coronary atherosclerotic disease Frontiers in Physiology | www.frontiersin.org 9 February 2019 | Volume 10 | Article 82 Jorge et al. Ischemia and Left Bundle Block on ST-segment changes induced by ST elevation myocardial infarction. Am. J. Vives-Borrás, M., Jorge, E., Amorós-Figueras, G., Millán, X., Arzamendi, D., and Cardiol. 113, 757–764. doi: 10.1016/j.amjcard.2013.11.034 Cinca, J. (2018). Summation and cancellation effects on QRS and ST-segment Opthof, T., Remme, C. A., Jorge, E., Noriega, F., Wiegerinck, R. F., Tasiam, A., et al. changes induced by simultaneous regional myocardial ischemia. Front. Physiol. (2017). Cardiac activation-repolarization patterns and ion channel expression 9:275. doi: 10.3389/fphys.2018.00275 mapping in intact isolated normal human hearts. Heart Rhythm 14, 265–272. Vives-Borrás, M., Moustafa, A.-H., Álvarez-García, J., Ferrero-Gregori, A., doi: 10.1016/j.hrthm.2016.10.010 Balcells, J., García-Picart, J., et al. (2017). Clinical and prognostic value of Rigol, M., Solanes, N., Fernandez-Armenta, J., Silva, E., Doltra, A., Duchateau, N., the electrocardiogram in patients with acute occlusion of the left circumflex et al. (2013). Development of a swine model of left bundle branch block coronary artery. Am. J. Cardiol. 120, 1487–1494. doi: 10.1016/j.amjcard.2017. for experimental studies of cardiac resynchronization therapy. J. Cardiovasc. 07.038 Transl. Res. 6, 616–622. doi: 10.1007/s12265-013-9464-1 Wagner, G. S., Macfarlane, P., Wellens, H., Josephson, M., Gorgels, A., Mirvis, Sgarbossa, E. B., Pinski, S. L., Barbagelata, A., Underwood, D. A., Gates, K. B., D. M., et al. (2009). AHA/ACCF/HRS recommendations for the standardization Topol, E. J., et al. (1996). Electrocardiographic diagnosis of evolving acute and interpretation of the electrocardiogram. J. Am. Coll. Cardiol. 53, 1003–1011. myocardial infarction in the presence of left bundle-branch block. N. Engl. J. doi: 10.1016/j.jacc.2008.12.016 Med. 334, 481–487. doi: 10.1056/NEJM199602223340801 Willems, J. L., Robles de Medina, E. O., Bernard, R., Coumel, P., Fisch, C., Shlipak, M. G., Lyons, W. L., Go, A. S., Chou, T. M., Evans, G. T., and Browner, Krikler, D., et al. (1985). Criteria for intraventricular conduction disturbances W. S. (1999). Should the electrocardiogram be used to guide therapy for patients and pre-excitation. World Health Organizational/International Society and with left bundle-branch block and suspected myocardial infarction? JAMA 281, federation for cardiology task force ad hoc. J. Am. Coll. Cardiol. 5, 1261–1275. 714–719. doi: 10.1016/S0735-1097(85)80335-1 Smith, S. W., Dodd, K. W., Henry, T. D., Dvorak, D. M., and Pearce, L. A. (2012). Diagnosis of ST-elevation myocardial infarction in the presence of left bundle Conflict of Interest Statement: The authors declare that the research was branch block with the ST-elevation to S-wave ratio in a modified Sgarbossa rule. conducted in the absence of any commercial or financial relationships that could Ann. Emerg. Med. 60, 766–776. doi: 10.1016/j.annemergmed.2012.07.119 be construed as a potential conflict of interest. Soto Iglesias, D., Duchateau, N., Kostantyn Butakov, C. B., Andreu, D., Fernandez- Armenta, J., Bijnens, B., et al. (2017). Quantitative analysis of electro- Copyright © 2019 Jorge, Solé-González, Amorós-Figueras, Arzamendi, Guerra, anatomical maps: application to an experimental model of left bundle branch Millán, Vives-Borrás and Cinca. This is an open-access article distributed under block/cardiac resynchronization therapy. IEEE J. Transl. Eng. Heal. Med. the terms of the Creative Commons Attribution License (CC BY). The use, 5:1900215. doi: 10.1109/JTEHM.2016.2634006 distribution or reproduction in other forums is permitted, provided the original Tabas, J. A., Rodriguez, R. M., Seligman, H. K., and Goldschlager, N. F. (2008). author(s) and the copyright owner(s) are credited and that the original publication Electrocardiographic criteria for detecting acute myocardial infarction in in this journal is cited, in accordance with accepted academic practice. No patients with left bundle branch block: a meta-analysis. Ann. Emerg. Med. 52, use, distribution or reproduction is permitted which does not comply with these 329.e1–336.e1. doi: 10.1016/j.annemergmed.2007.x12.006 terms. Frontiers in Physiology | www.frontiersin.org 10 February 2019 | Volume 10 | Article 82