Epicardial Regions Research Articles

Epicardial origin of cardiac arrhythmias: clinical evidences and pathophysiology.

Recent developments in imaging, mapping, and ablation techniques have shown that the epicardial region of the heart is a key player in the occurrence of ventricular arrhythmic events in several cardiac diseases, such as Brugada syndrome, arrhythmogenic cardiomyopathy, or dilated cardiomyopathy. At the atrial level as well, the epicardial region has emerged as an important determinant of the substrate of atrial fibrillation, pointing to common underlying pathophysiological mechanisms. Alteration in the gradient of repolarization between myocardial layers favouring the occurrence of re-entry circuits has largely been described. The fibro-fatty infiltration of the subepicardium is another shared substrate between ventricular and atrial arrhythmias. Recent data have emphasized the role of the epicardial reactivation in the formation of this arrhythmogenic substrate. There are new evidences supporting this structural remodelling process to be regulated by the recruitment of epicardial progenitor cells that can differentiate into adipocytes or fibroblasts under various stimuli. In addition, immune-inflammatory processes can also contribute to fibrosis of the subepicardial layer. A better understanding of such ‘electrical fragility’ of the epicardial area will open perspectives for novel biomarkers and therapeutic strategies. In this review article, a pathophysiological scheme of epicardial-driven arrhythmias will be proposed.

Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair

Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair.

Scar Formation with Decreased Cardiac Function Following Ischemia/Reperfusion Injury in 1 Month Old Swine.

Studies in mice show a brief neonatal period of cardiac regeneration with minimal scar formation, but less is known about reparative mechanisms in large mammals. A transient cardiac injury approach (ischemia/reperfusion, IR) was used in weaned postnatal day (P)30 pigs to assess regenerative repair in young large mammals at a stage when cardiomyocyte (CM) mitotic activity is still detected. Female and male P30 pigs were subjected to cardiac ischemia (1 h) by occlusion of the left anterior descending artery followed by reperfusion, or to a sham operation. Following IR, myocardial damage occurred, with cardiac ejection fraction significantly decreased 2 h post-ischemia. No improvement or worsening of cardiac function to the 4 week study end-point was observed. Histology demonstrated CM cell cycling, detectable by phospho-histone H3 staining, at 2 months of age in multinucleated CMs in both sham-operated and IR pigs. Inflammation and regional scar formation in the epicardial region proximal to injury were observed 4 weeks post-IR. Thus, pigs subjected to cardiac IR at P30 show myocardial damage with a prolonged decrease in cardiac function, formation of a regional scar, and increased inflammation, but do not regenerate myocardium even in the presence of CM mitotic activity.

Mapping and Ablation of Arrhythmias from Uncommon Sites (Aortic Cusp, Pulmonary Artery, and Left Ventricular Summit).

Despite advances in our understanding of the relevant anatomy and mapping and catheter ablation techniques of idiopathic outflow tract ventricular arrhythmias, challenging sites for catheter ablation remain the aortic cusps, pulmonary artery, and notably the left ventricular summit. A systematic approach should be used to direct mapping efforts efficiently between endocardial, coronary venous, and epicardial sites. Foci at the left ventricular summit, particularly intraseptal and at the inaccessible epicardial region, remain difficult to reach and when percutaneous techniques fail, surgical ablation remains an option but with risk of late coronary artery stenosis.

The evaluation of epicardial adipose tissue radiodensity according to age

Aim: The grading of fatty degeneration by cardiac computerized tomography (CCT) is an important bioradiological marker to discriminate biological characteristics. Epicardial adipose tissue (EAT) degeneration has been accused of causing heart disease. However, the relationship between age and EAT radiodensity is not well known. In this study we examined epicardial adipose tissue radiodensity with CCT. Methods: A total of 147 subjects who underwent contrast-enhanced evaluation of coronary arteries with CCT between Jun 2018-July 2019 due to intermediate probability of coronary artery disease (CAD) were included in this retrospective cohort study. The radiodensities of three epicardial regions (right atrioventricular groove, posterior interventricular groove, and anterior epicardial area) and individual subxiphoid fat radiodensity ratios were obtained. Group comparisons were made according to 10-year-periods (between 10- 80 years of age). Results: We found that epicardial adipose tissue/ subxiphoid fat radiodensity ratio decreased with increasing age. After the 3rd decade, we detected a negative correlation between EAT/subxiphoid fat radiodensity ratio (r=-0.11). The radiodensity ratios of patients between 20-30 and 30-40 years of age in the LCX, RCA and anterior epicardial regions were 1.71 (0.14) and 1.06 (0.40) (P

Feasibility of percutaneous epicardial mapping and ablation for refractory atrial fibrillation: Insights into substrate and lesion transmurality

Recurrences of atrial fibrillation (AF) after ablation have been attributed to conduction gaps and nontransmural ablation lesions. The purpose of this study was to assess the feasibility of adjunctive percutaneous mapping of the epicardial regions of the left atrium to characterize the transmural extent of substrate and ablation lesions. Between 2014 and 2018, combined epicardial and endocardial mapping of AF was performed in 18 patients via an inferior subxiphoid percutaneous approach (16 with previously failed ablation procedures and 2 patients with long-standing persistent AF) at 2 centers. Epicardial substrate mapping was compared with endocardial mapping to assess transmural uniformity. Of 18 patients, 4 (22%) demonstrated nontransmural atrial low-voltage regions with relative epicardial sparing in the left atrial posterior wall. Transmural isolation of the posterior wall was achieved after an endocardial "box" lesion set in 6/9 (67%), guided by epicardial voltage data, while epicardial and endocardial dissociation during AF was observed in 1 patient. In 3 patients, epicardial capture along the endocardial pulmonary vein lesion set despite endocardial capture loss and bidirectional block was observed. Two cases of mitral flutter were terminated from the epicardium. A balloon was positioned in the pericardial space in 6 patients for esophageal protection during ablation. A percutaneous epicardial approach for mapping and ablation of the left atrium is feasible in the electrophysiology laboratory during endocardial catheter ablation for AF and may be useful as an adjunctive approach in refractory cases. High-density epicardial mapping can provide direct evidence of nonuniform lesion and substrate transmurality of the human left atrium before and after ablation.

Contraction and intracellular calcium transport in epicardial and endocardial ventricular myocytes from streptozotocin-induced diabetic rat

Introduction: Diabetes mellitus (DM) is a global health problem. According to the International Diabetes Federation, 424.9 million people suffered from DM in 2017 and this number is expected to rise to 628.6 million by 2045. Although diabetes can affect every organ in the body, cardiovascular disease is a major cause of death and disability in people with diabetes. Diabetic patients frequently suffer from systolic and diastolic dysfunction. Within the ventricles, the electromechanical properties of cardiac myocytes vary transmurally. Aims and Objectives: The aim of this study was to investigate contraction and Ca2+ transport in epicardial (EPI) and endocardial (ENDO) myocytes from the left ventricle in the streptozotocin (STZ) – induced diabetic rat heart. Materials and Methods: Experiments were performed 5-6 months after STZ treatment. Ventricular myocytes were isolated by enzymic and mechanical dispersal techniques from EPI and ENDO regions of the left ventricle. Contraction and free intracellular Ca2+ concentration [Ca2+]i were measured by video edge detection and fluorescence photometry techniques, respectively. Results: Myocyte length and calculated surface area were smaller in EPI-STZ compared to EPI-CON. Time to peak (TPK) shortening was prolonged in EPI-STZ compared to EPI-CON and in ENDO-STZ compared to ENDO-CON myocytes. Time to half (THALF) relaxation of shortening was prolonged in EPI-STZ compared to EPI-CON. TPK Ca2+ transient was prolonged in EPI-STZ compared to EPI-CON, ENDO-STZ compared to ENDO-CON, ENDO-STZ compared to EPI-STZ and in ENDO-CON compared to EPI-CON myocytes. THALF decay of the Ca2+ transient was prolonged in ENDO-STZ compared to ENDO-CON. Fractional release of Ca2+ was increased in ENDO-STZ compared to ENDO-CON and in ENDO-STZ compared to EPI-STZ. Recovery of the Ca2+ transient was prolonged in ENDO-STZ compared to ENDO-CON. Conclusion: In conclusion the kinetics of contraction and Ca2+ transient and fractional release of Ca2+ from the sarcoplasmic reticulum are altered to different extents in EPI and ENDO myocytes from STZ-induced diabetic rat.

Myocardial oxygen balance during acute normovolemic hemodilution: A novel compartmental modeling approach

BackgroundHemodilution was introduced initially as a blood conservation technique to reduce allogeneic blood transfusion in patients undergoing surgical procedures. Although the technique has been approved by the National Institute of Health consensus panel, limits of hemodilution under anesthetic conditions have not been established as they have in animal models. MethodsA novel multi-compartmental modeling approach has been proposed that includes the effect of anesthesia to quantify the effect of hemodilution on myocardial oxygen balance during myocardial ischemia. ResultsThe results showed that isovolemic hemodilution would cause detrimental effects around a hematocrit of 15%. Even though the fall in oxygen content caused by the decrease in hemoglobin concentration was compensated by an increase in coronary blood flow induced by hypoxic vasodilation and decreased viscosity, the endocardial tissue received less oxygen compared to the epicardial regions, and this sub-endocardial ischemia eventually led to cardiac failure. Statistical analysis also showed that the type of acellular replacement fluid failed to affect the heart rate, the stroke index or the cardiac index during hemodilution, and supplemental oxygen improved the endocardial oxygen supply. ConclusionThe model validates the clinical conclusions that sub-endocardial ischemia causes cardiac failure under extreme hemodilution conditions and the model can also be easily integrated into other human simulators.

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD.

Segmentation of Left and Right Ventricles in Cardiac MRI Using Active Contours.

Segmentation of left and right ventricles plays a crucial role in quantitatively analyzing the global and regional information in the cardiac magnetic resonance imaging (MRI). In MRI, the intensity inhomogeneity and weak or blurred object boundaries are the problems, which makes it difficult for the intensity-based segmentation methods to properly delineate the regions of interests (ROI). In this paper, a hybrid signed pressure force function (SPF) is proposed, which yields both local and global image fitted differences in an additive fashion. A characteristic term is also introduced in the SPF function to restrict the contour within the ROI. The overlapping dice index and Hausdorff-Distance metrics have been used over cardiac datasets for quantitative validation. Using 2009 LV MICCAI validation dataset, the proposed method yields DSC values of 0.95 and 0.97 for endocardial and epicardial contours, respectively. Using 2012 RV MICCAI dataset, for the endocardial region, the proposed method yields DSC values of 0.97 and 0.90 and HD values of 8.51 and 7.67 for ED and ES, respectively. For the epicardial region, it yields DSC values of 0.92 and 0.91 and HD values of 6.47 and 9.34 for ED and ES, respectively. Results show its robustness in the segmentation application of the cardiac MRI.

Geographical predisposition influences on the distribution and tissue characterisation of eccentric coronary plaques in non-branching coronary arteries: cross-sectional study of coronary plaques analysed by intravascular ultrasound.

BackgroundWe investigated the influence of geographical predisposition on the spatial distribution and composition of coronary plaques.MethodsThirty coronary arteries were evaluated. A total of 1441 cross-sections were collected from intravascular ultrasound (IVUS) and radio-frequency signal-based virtual histology (VH-IVUS) imaging. To exclude complex geographical effects of side branches and to localise the plaque distribution, we analysed only eccentric plaques in non-branching regions. The spatial distribution of eccentric plaques in the coronary artery was classified into myocardial, lateral, and epicardial regions. The composition of eccentric plaques was analysed using VH-IVUS.ResultsThe plaque was concentric in 723 sections (50.2%) and eccentric in 718 (49.9%). Eccentric plaques were more frequently distributed towards the myocardial side than towards the epicardial side (46.7 ± 7.5% vs. 12.5 ± 4.2%, p = 0.003). No significant difference was observed between the myocardial and lateral sides (46.7 ± 7.5% vs. 20.8 ± 5.0%) or between the lateral and epicardial sides. Eccentric thin-capped fibroatheromas were more frequently distributed towards the myocardial side than towards the lateral side (p = 0.024) or epicardial side (p = 0.005).ConclusionGeographical predisposition is associated with distribution, tissue characterisation, and vulnerability of plaques in non-branching coronary arteries.

Experimental Study of Kinematic Activity of Left Ventricular Myocardium.

A method of invasive and non-invasive examination of epicardial motion was tested on domestic pigs (n=15). The invasive study employed a contact kinematic sensor of the epicardial wall motion, which determined the amplitude, velocity, and angular parameters of examined epicardial region. A non-invasive assessment of the epicardial kinematics based on echocardiographic 2D Velocity Vector Imaging and ECG recoding used to determine the heart electrical axis. The 4-chamber views were uses to analyze the longitudinal displacements of lateral wall of the left ventricle at the basal, mid, and apical segments. In addition, the radial displacements were determined in short axis projections at basal and apical segments as well as at the level of papillary muscles. The animals with normal or horizontal heart's electrical axis demonstrated similar displacement of the epicardium along X-axis and in longitudinal direction, while displacement along Y-axis corresponded to that in radial direction. The combined invasive and non-invasive approach in measurement of epicardium motion makes it possible to quantify the kinematic epicardial activity.

Cardiac biology: A protein for healing infarcted hearts.

Human heart tissue has minimal ability to regenerate following injury. But the protein Fstl1, which is normally expressed in the heart's epicardial region, has now been shown to induce regeneration following heart attack. See Article p.479 Human heart tissue has a limited capacity to regenerate but recent studies have suggested that the epicardium might preserve function of the adult myocardium following injury to some extent, possibly by providing myogenic progenitors. This study identifies the secreted factor follistatin-like 1 (FSTL1) as a regenerative factor that is normally present in healthy epicardium, but lost following myocardial infarction, suggesting a mechanism whereby injury diminishes the regenerative potency of the mammalian heart. Reconstitution of FSTL1 by an engineered epicardial biomaterial improved cardiac function in animal models of myocardial infarction, with evidence of cardiomyocyte regeneration amenable to clinical translation.

Computational analysis of the electromechanical consequences of short QT syndrome.

Computational analysis of the electromechanical consequences of short QT syndrome.

OR24: MONOCYTE RECRUITMENT TO HUMAN LEUKOCYTE ANTIGEN CLASS I ANTIBODY-ACTIVATED ENDOTHELIAL CELLS IS DEPENDENT UPON MTOR

Aim A hallmark of antibody (Ab)-mediated rejection is the presence of intravascular monocytes in the allograft. The purpose of this study was to determine the effects of rapamycin on monocyte recruitment and M1/M2 polarization in a clinically relevant in vivo model of antibody mediated-rejection (AMR). Methods Rag1 knock-out mice heterotopically transplanted with mismatched donor hearts were treated with rapamycin and received passive transfer of anti-donor antibodies (MHC I Ab). After 10 days, grafts were examined for histological features of AMR including microvascular inflammation and swelling and mononuclear cell infiltration by immunohistochemistry. Cross-sections of allograft tissue were stained for Mac-2 to assess myeloid infiltration, and for Arginase 1, a marker of polarized M2 macrophage subset. In vitro experiments were used to confirm the role of mTOR in monocyte recruitment to HLA-activated primary human aortic endothelial cells. Results The positive control group, which received anti-donor MHC antibodies, manifested with capillary injury, epicardial and pericardial damage, as well as infiltrating mononuclear cells into the graft vasculature and epicardial regions. Mice in the experimental group, which received daily intraperitoneal rapamycin treatment followed by biweekly anti-donor MHC antibodies, demonstrated reduced intra-graft cellularity and endothelial damage. HE a marker of inflammatory macrophages. Arginase 1 staining revealed M2 + macrophages were present in MHC Ab-treated allografts, and furthermore, the distribution of this subset partially overlapped with that of Mac-2. Though Mac-2 staining was found diffusely throughout the allograft, Arg1 positive macrophages localized primarily to the pericardium and fibrotic regions. Conclusion Antibody-mediated rejection drives the polarization of M2 macrophages, which can promote cell proliferation and tissue repair. mTOR blockade prevents monocyte recruitment to activated endothelium of cardiac allografts. S. Salehi: Grant/Research Support; Company/Organization; NIH.

Impact of hypokalemia on electromechanical window, excitation wavelength and repolarization gradients in guinea-pig and rabbit hearts.

Normal hearts exhibit a positive time difference between the end of ventricular contraction and the end of QT interval, which is referred to as the electromechanical (EM) window. Drug-induced prolongation of repolarization may lead to the negative EM window, which was proposed to be a novel proarrhythmic marker. This study examined whether abnormal changes in the EM window may account for arrhythmogenic effects produced by hypokalemia. Left ventricular pressure, electrocardiogram, and epicardial monophasic action potentials were recorded in perfused hearts from guinea-pig and rabbit. Hypokalemia (2.5 mM K+) was found to prolong repolarization, reduce the EM window, and promote tachyarrhythmia. Nevertheless, during both regular pacing and extrasystolic excitation, the increased QT interval invariably remained shorter than the duration of mechanical systole, thus yielding positive EM window values. Hypokalemia-induced arrhythmogenicity was associated with slowed ventricular conduction, and shortened effective refractory periods, which translated to a reduced excitation wavelength index. Hypokalemia also evoked non-uniform prolongation of action potential duration in distinct epicardial regions, which resulted in increased spatial variability in the repolarization time. These findings suggest that arrhythmogenic effects of hypokalemia are not accounted for by the negative EM window, and are rather attributed to abnormal changes in ventricular conduction times, refractoriness, excitation wavelength, and spatial repolarization gradients.

Relationship between MDCT-imaged myocardial fat and ventricular tachycardia substrate in arrhythmogenic right ventricular cardiomyopathy.

BackgroundMyocardial fibrofatty infiltration is a milieu for ventricular tachycardia (VT) in arrhythmogenic right ventricular cardiomyopathy (ARVC) and can be depicted as myocardial hypodensity on contrast‐enhanced multidetector computed tomography (MDCT) with high spatial and temporal resolution. This study aimed to assess the relationship between MDCT‐imaged myocardial fat and VT substrate in ARVC.Methods and ResultsWe studied 16 patients with ARVC who underwent ablation and preprocedural MDCT. High‐resolution imaging data were processed and registered to high‐density endocardial and epicardial maps in sinus rhythm on 3‐dimensional electroanatomic mapping (3D‐EAM) (626±335 and 575±279 points/map, respectively). Analysis of the locations of low‐voltage and fat segmentation included the following endocardial and epicardial regions: apex, mid (anterior, lateral, inferior), and basal (anterior, lateral, inferior). The location of local abnormal ventricular activities (LAVA) was compared with fat distribution. RV myocardial fat was successfully segmented and integrated with 3D‐EAM in all patients. The κ agreement test demonstrated a good concordance between the epicardial low voltage and fat (κ=0.69, 95% CI 0.54 to 0.84), but fair concordance with the endocardium (κ=0.41, 95% CI 0.27 to 0.56). The majority of LAVA (520/653 [80%]) were located within the RV fat segmentation, of which 90% were not farther than 20 mm from its border. Registration of MDCT allowed direct visualization of the coronary arteries, thus avoiding coronary damage during epicardial radiofrequency delivery.ConclusionsThe integration of MDCT‐imaged myocardial fat with 3D‐EAM provides valuable information on the extent and localization of VT substrate and demonstrates ablation targets clustering in its border region.

QT Interval Heterogeneities Induced Through Local Epicardial Warming/Cooling. An Experimental Study

Introduction and objectivesAbnormal QT interval durations and dispersions have been associated with increased risk of ventricular arrhythmias. The present study examines the possible arrhythmogenic effect of inducing QT interval variations through local epicardial cooling and warming. MethodsIn 10 isolated rabbit hearts, the temperatures of epicardial regions of the left ventricle were modified in a stepwise manner (from 22°C to 42°C) with simultaneous electrogram recording in these regions and in others of the same ventricle. QT and activation-recovery intervals were determined during sinus rhythm, whereas conduction velocity and ventricular arrhythmia induction were determined during programmed stimulation. ResultsIn the area modified from baseline temperature (37°C), the QT (standard deviation) was prolonged with maximum hypothermia (195 [47] vs 149 [12] ms; P<.05) and shortened with hyperthermia (143 [18] vs 152 [27] ms; P<.05). The same behavior was displayed for the activation-recovery interval. The conduction velocity decreased with hypothermia and increased with hyperthermia. No changes were seen in the other unmodified area. Repetitive responses were seen in 5 experiments, but no relationship was found between their occurrence and hypothermia or hyperthermia (P>.34). ConclusionsIn the experimental model employed, local variations in the epicardial temperature modulate the QT interval, activation-recovery interval, and conduction velocity. Induction of heterogeneities did not promote ventricular arrhythmia occurrence.

Heterogeneidades inducidas en el intervalo QT mediante enfriamiento/calentamiento epicárdico local. Estudio experimental

Introduction and objectivesAbnormal QT interval durations and dispersions have been associated with increased risk of ventricular arrhythmias. The present study examines the possible arrhythmogenic effect of inducing QT interval variations through local epicardial cooling and warming. MethodsIn 10 isolated rabbit hearts, the temperatures of epicardial regions of the left ventricle were modified in a stepwise manner (from 22°C to 42°C) with simultaneous electrogram recording in these regions and in others of the same ventricle. QT and activation-recovery intervals were determined during sinus rhythm, whereas conduction velocity and ventricular arrhythmia induction were determined during programmed stimulation. ResultsIn the area modified from baseline temperature (37°C), the QT (standard deviation) was prolonged with maximum hypothermia (195 [47] vs 149 [12] ms; P<.05) and shortened with hyperthermia (143 [18] vs 152 [27] ms; P<.05). The same behavior was displayed for the activation-recovery interval. The conduction velocity decreased with hypothermia and increased with hyperthermia. No changes were seen in the other unmodified area. Repetitive responses were seen in 5 experiments, but no relationship was found between their occurrence and hypothermia or hyperthermia (P>.34). ConclusionsIn the experimental model employed, local variations in the epicardial temperature modulate the QT interval, activation-recovery interval, and conduction velocity. Induction of heterogeneities did not promote ventricular arrhythmia occurrence.Full English text available from: www.revespcardiol.org/en

Dependence of phase-2 reentry and repolarization dispersion on epicardial and transmural ionic heterogeneity: a simulation study

Phase-2 reentry (P2R) is a local arrhythmogenic phenomenon where electrotonic current propagates from a spike-and-dome action potential region to re-excite a loss-of-dome action potential region. While ionic heterogeneity has been shown to underlie P2R within the epicardium and has been hypothesized to occur transmurally, we are unaware of any study that has investigated the effects of combining these heterogeneities as they occur in the heart. Thus, we tested the hypothesis that P2R can result by either epicardial or transmural heterogeneity and that the realistic combination of the two would increase the likelihood of P2R. We used computational ionic models of cardiac myocyte dynamics to investigate initiation and development of P2R in simulated tissues with different ionic heterogeneities. In one-dimensional transmural cable simulations, P2R occurred when the conductance of the transient outward current in the epicardial region was near the range for which epicardial action potentials switched intermittently between spike-and-dome and loss-of-dome morphologies. Phase-2 reentry was more likely in two-dimensional tissue simulations by both epicardial and transmural heterogeneity and could expand beyond its local initiation site to create a macroscopic reentry. The characteristics and stability of action potential morphology in the epicardium are important determinants of the occurrence of both transmural and epicardial P2R and its associated arrhythmogenesis.