Prevalence and electrocardiographic and electrophysiological characteristics of idiopathic ventricular arrhythmias originating from the septal left ventricular summit.

INTRODUCTION: The left ventricular summit (LVS) is the highest point on the epicardial surface of the left ventricle. A part of the LVS that is located between the left coronary arteries (lateral-LVS) is one of the major sites of idiopathic ventricular arrhythmia (VA) origins. Some idiopathic epicardial VAs can be ablated at endocardial sites adjacent to the epicardial area septal to the lateral-LVS (septal-LVS). This study examined the prevalence and electrocardiographic and electrophysiological characteristics of septal-LVS VAs. METHODS: We studied consecutive patients with idiopathic VAs originating from the LVS (67 patients) and aortic root (93 patients). RESULTS: Based on the ablation results, among 67 LVS VAs, 54 were classified as lateral and 13 as septal-LVS VAs. As compared with the lateral-LVS VAs, the septal-LVS VAs were characterized by a greater prevalence of left bundle branch block with left inferior-axis QRS pattern, later precordial transition, lower R-wave amplitude ratio in leads III to II, lower Q-wave amplitude ratio in leads aVL to aVR, and later local ventricular activation time relative to the QRS onset during VAs (V-QRS) in the great cardiac vein. The electrocardiographic and electrophysiological characteristics of the septal-LVS VAs were similar to those of the aortic root VAs. However, the V-QRS at the successful ablation site was significantly later during the septal-LVS VAs than aortic root VAs (p < .0001). The precordial transition was significantly later during the septal-LVS VAs than aortic root VAs (p < .05). CONCLUSIONS: Septal-LVS VAs are considered a distinct subgroup of idiopathic VAs originating from the left ventricular outflow tract.

A Large Postmortem Database of COVID-19 Patients Can Inform Disease Research and Public Policy Decision Making.

CONTEXT.­: Autopsies performed on COVID-19 patients have provided critical information about SARS-CoV-2's tropism, mechanisms of tissue injury, and the spectrum of disease. OBJECTIVE.­: To provide an updated database of postmortem disease in COVID-19 patients, assess relationships among clinical and pathologic variables, evaluate the accuracy of death certification, and correlate disease variables to causes of death. DESIGN.­: The 272 postmortem examinations reported in this paper were submitted by 14 pathologists from 9 medical or forensic institutions across the United States. The study spans the eras of the 3 principal COVID-19 strains and incorporates surveyed demographic, clinical, and postmortem data from decedents infected with SARS-CoV-2, including primary and contributing causes of death. It is the largest database of its kind to date. RESULTS.­: Demographics of the decedents reported here correspond well to national statistics. Primary causes of death as determined by autopsy and official death certificates were significantly correlated. When specifically cited disease conditions found at autopsy were correlated with COVID-19 versus non-COVID-19 death, only lung findings characteristic of SARS-CoV-2 infection or the absence of lung findings were significantly associated. CONCLUSIONS.­: Changes in hospitalization and disease likely stem from longer lifespans after COVID-19 diagnosis and alteration in treatment approaches. Although Omicron variants preferentially replicate in the upper airways, autopsied patients who died of COVID-19 in that time period showed the same lung damage as earlier decedents. Most importantly, findings suggest that there are still unelucidated risk factors for death from COVID-19 including possibly genetic susceptibility.

Structurally constrained and pathology-aware convolutional transformer generative adversarial network for virtual histology staining of human coronary optical coherence tomography images.

Significance: There is a significant need for the generation of virtual histological information from coronary optical coherence tomography (OCT) images to better guide the treatment of coronary artery disease (CAD). However, existing methods either require a large pixel-wise paired training dataset or have limited capability to map pathological regions. Aim: The aim of this work is to generate virtual histological information from coronary OCT images, without a pixel-wise paired training dataset while capable of providing pathological patterns. Approach: We design a structurally constrained, pathology-aware, transformer generative adversarial network, namely structurally constrained pathology-aware convolutional transformer generative adversarial network (SCPAT-GAN), to generate virtual stained H&E histology from OCT images. We quantitatively evaluate the quality of virtual stained histology images by measuring the Fréchet inception distance (FID) and perceptual hash value (PHV). Moreover, we invite experienced pathologists to evaluate the virtual stained images. Furthermore, we visually inspect the virtual stained image generated by SCPAT-GAN. Also, we perform an ablation study to validate the design of the proposed SCPAT-GAN. Finally, we demonstrate 3D virtual stained histology images. Results: Compared to previous research, the proposed SCPAT-GAN achieves better FID and PHV scores. The visual inspection suggests that the virtual histology images generated by SCPAT-GAN resemble both normal and pathological features without artifacts. As confirmed by the pathologists, the virtual stained images have good quality compared to real histology images. The ablation study confirms the effectiveness of the combination of proposed pathological awareness and structural constraining modules. Conclusions: The proposed SCPAT-GAN is the first to demonstrate the feasibility of generating both normal and pathological patterns without pixel-wisely supervised training. We expect the SCPAT-GAN to assist in the clinical evaluation of treating the CAD by providing 2D and 3D histopathological visualizations.

Subclinical maternal autoimmune disease leading to congenital high degree atrioventricular block: Case report and review of the literature.

Maternal autoimmune disease is the most common cause of congenital heart block (CHB), a rare illness characterized by fibrosis and calcification of the fetal atrioventricular (AV) node due to maternal autoantibodies anti-SSA/Ro and anti-SSB/La. We report the full autopsy and clinical information on a female neonate with high degree AV block and calcification in the AV node, atrial approaches to the AV node, and both right and left bundle branches, born to a 27-year-old female with subclinical autoimmune disease.

The interplay between sex, time of day, fasting status, and their impact on cardiac mitochondrial structure, function, and dynamics.

Mitochondria morphology and function, and their quality control by mitophagy, are essential for heart function. We investigated whether these are influenced by time of the day (TOD), sex, and fed or fasting status, using transmission electron microscopy (EM), mitochondrial electron transport chain (ETC) activity, and mito-QC reporter mice. We observed peak mitochondrial number at ZT8 in the fed state, which was dependent on the intrinsic cardiac circadian clock, as hearts from cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit different TOD responses. In contrast to mitochondrial number, mitochondrial ETC activities do not fluctuate across TOD, but decrease immediately and significantly in response to fasting. Concurrent with the loss of ETC activities, ETC proteins were decreased with fasting, simultaneous with significant increases of mitophagy, mitochondrial antioxidant protein SOD2, and the fission protein DRP1. Fasting-induced mitophagy was lost in CBK mice, indicating a direct role of BMAL1 in regulating mitophagy. This is the first of its kind report to demonstrate the interactions between sex, fasting, and TOD on cardiac mitochondrial structure, function and mitophagy. These studies provide a foundation for future investigations of mitochondrial functional perturbation in aging and heart diseases.

Consensus statement on the processing, interpretation and reporting of temporal artery biopsy for arteritis.

Giant cell arteritis (GCA) is the most common systemic vasculitis in adults in Europe and North America, typically involving the extra-cranial branches of the carotid arteries and the thoracic aorta. Despite advances in noninvasive imaging, temporal artery biopsy (TAB) remains the gold standard for establishing a GCA diagnosis. The processing of TAB depends largely on individual institutional protocol, and the interpretation and reporting practices vary among pathologists. To address this lack of uniformity, the Society for Cardiovascular Pathology formed a committee tasked with establishing consensus guidelines for the processing, interpretation, and reporting of TAB specimens, based on the existing literature. This consensus statement includes a discussion of the differential diagnoses including other forms of arteritis and noninflammatory changes of the temporal artery.

De novo heterozygous pathogenic FBN1 variant in an autopsy case of multiple aneurysms and right renal artery dissection: a case report.

Background: Marfan syndrome is a potentially fatal inherited autosomal dominant condition impacting the cardiovascular and the skeletal system with an estimated 25% cases caused by sporadic genetic variations. Given the genetic inheritance pattern, an autopsy of probands with Marfan syndrome-associated mortality is critical to establish the phenotypic expression and clinical implications of the particular genetic variant, especially for first-degree relatives. We present the findings of a Marfan syndrome proband decedent presenting with sudden onset abdominal pain and unexplained retroperitoneal abdominal hemorrhage. Methods: An autopsy was performed to inform the blood relatives of the phenotypic expression and penetrance of the potentially heritable condition. A clinical laboratory improvement amendment (CLIA)-certified clinical grade genetic sequencing was performed to identify pathogenic variants in genes associated with aortopathy. Results: The autopsy showed intra-abdominal and retroperitoneal hemorrhage due to infarction of the right kidney caused by dissection of the right renal artery. Genetic testing identified a heterozygous pathogenic FBN1 gene variant. The specific variant is FBN1 NM_000138.4 c.2953G > A p.(Gly985Arg). Conclusions: We report a case of a previously undiagnosed Marfan syndrome death due to a de novo FBN1 variant, c.2953G > A.

Cardiogenic shock in a woman with a mitochondrial cardiomyopathy: a case report.

Background: Mitochondrial cardiomyopathy (MCM) is an alteration in cardiac structure and function caused by gene mutations or deletions affecting components of the mitochondrial respiratory chain. We report a case of MCM presenting as cardiogenic shock, ultimately requiring left ventricular assist device (LVAD) placement. Case summary: A 35-year-old woman with chronic weakness and non-ischaemic cardiomyopathy, on home dobutamine, was referred to our institution for heart transplantation evaluation. She was admitted to the hospital for suspected cardiogenic shock after laboratory tests revealed a lactate level of 5.4 mmol/L (ref: 0.5-2.2 mmol/L). Her hospital course was complicated by persistently undulating lactate levels (0.2-8.6 mmol/L) that increased with exertion and did not correlate with mixed venous oxygen saturation measurements obtained from a pulmonary artery catheter. Electrodiagnostic testing demonstrated a proximal appendicular and axial myopathy. A left deltoid muscle biopsy was performed that demonstrated evidence of a mitochondrial disease on light and electron microscopy. Muscle genetic testing revealed two large-scale mitochondrial deoxyribonucleic acid sequence deletions, confirming the diagnosis of MCM. She subsequently underwent LVAD placement, which was complicated by significant right ventricular failure requiring early mechanical support. She was ultimately discharged home with chronic inotropic support. Discussion: Mitochondrial cardiomyopathy in adults is a diagnostic and therapeutic challenge. Prompt diagnosis should be made in patients with unknown causes of heart failure via skeletal muscle histopathology guided by electrodiagnostic studies, and targeted genetic testing in affected tissue. Outcomes in adult MCM patients who receive an LVAD are unknown and warrant further investigation.

Unsupervised mRNA-seq classification of heart transplant endomyocardial biopsies.

BACKGROUND: Endomyocardial biopsy (EMB) is currently considered the gold standard for diagnosing cardiac allograft rejection. However, significant limitations related to histological interpretation variability are well-recognized. We sought to develop a methodology to evaluate EMB solely based on gene expression, without relying on histology interpretation. METHODS: Sixty-four EMBs were obtained from 47 post-heart transplant recipients, who were evaluated for allograft rejection. EMBs were subjected to mRNA sequencing, in which an unsupervised classification algorithm was used to identify the molecular signatures that best classified the EMBs. Cytokine and natriuretic peptide peripheral blood profiling was also performed. Subsequently, we performed gene network analysis to identify the gene modules and gene ontology to understand their biological relevance. We correlated our findings with the unsupervised and histological classifications. RESULTS: Our algorithm classifies EMBs into three categories based solely on clusters of gene expression: unsupervised classes 1, 2, and 3. Unsupervised and histological classifications were closely related, with stronger gene module-phenotype correlations for the unsupervised classes. Gene ontology enrichment analysis revealed processes impacting on the regulation of cardiac and mitochondrial function, immune response, and tissue injury response. Significant levels of cytokines and natriuretic peptides were detected following the unsupervised classification. CONCLUSION: We have developed an unsupervised algorithm that classifies EMBs into three distinct categories, without relying on histology interpretation. These categories were highly correlated with mitochondrial, immune, and tissue injury response. Significant cytokine and natriuretic peptide levels were detected within the unsupervised classification. If further validated, the unsupervised classification could offer a more objective EMB evaluation.

Coronary Stent Abscess in the Setting of Arteriovenous Graft Infection following COVID-19: An Autopsy Case Report.

While rare, coronary stent infections present with significant mortality-with most infections and further complications occurring within months of percutaneous coronary intervention (PCI). Here, we discuss a post-COVID-19 patient who presented approximately one year after PCI for declotting of an arteriovenous graft (AVG). Upon admission, the patient was found to be bacteremic with multilobar pneumonia and an infection of the AVG. Empiric antibiotics were started, and blood cultures were subsequently positive for MRSA. Removal of the AVG was unsuccessful, and two days after admission, the patient passed. Autopsy revealed a perivascular abscess in the RCA near the origin of the stent with a ground section of the RCA with stent revealing abundant calcific atherosclerosis and marked necrosis of the artery wall. The cause of death was determined to be sepsis complicating coronary artery disease and chronic renal failure.

Cardiomyocyte ZKSCAN3 regulates remodeling following pressure-overload.

Autophagy is important for protein and organelle quality control. Growing evidence demonstrates that autophagy is tightly controlled by transcriptional mechanisms, including repression by zinc finger containing KRAB and SCAN domains 3 (ZKSCAN3). We hypothesize that cardiomyocyte-specific ZKSCAN3 knockout (Z3K) disrupts autophagy activation and repression balance and exacerbates cardiac pressure-overload-induced remodeling following transverse aortic constriction (TAC). Indeed, Z3K mice had an enhanced mortality compared to control (Con) mice following TAC. Z3K-TAC mice that survived exhibited a lower body weight compared to Z3K-Sham. Although both Con and Z3K mice exhibited cardiac hypertrophy after TAC, Z3K mice exhibited TAC-induced increase of left ventricular posterior wall thickness at end diastole (LVPWd). Conversely, Con-TAC mice exhibited decreases in PWT%, fractional shortening (FS%), and ejection fraction (EF%). Autophagy genes (Tfeb, Lc3b, and Ctsd) were decreased by the loss of ZKSCAN3. TAC suppressed Zkscan3, Tfeb, Lc3b, and Ctsd in Con mice, but not in Z3K. The Myh6/Myh7 ratio, which is related to cardiac remodeling, was decreased by the loss of ZKSCAN3. Although Ppargc1a mRNA and citrate synthase activities were decreased by TAC in both genotypes, mitochondrial electron transport chain activity did not change. Bi-variant analyses show that while in Con-Sham, the levels of autophagy and cardiac remodeling mRNAs form a strong correlation network, such was disrupted in Con-TAC, Z3K-Sham, and Z3K-TAC. Ppargc1a also forms different links in Con-sham, Con-TAC, Z3K-Sham, and Z3K-TAC. We conclude that ZKSCAN3 in cardiomyocytes reprograms autophagy and cardiac remodeling gene transcription, and their relationships with mitochondrial activities in response to TAC-induced pressure overload.

Percutaneous debulking of tricuspid valve endocarditis in severe COVID-19 pneumonia after prolonged venovenous extracorporeal membrane oxygenation with right-ventricular support: a case series.

Background: Over the past 2 years, the utilization of venovenous extracorporeal membrane oxygenation (VV-ECMO) for the treatment of coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) has increased. While supporting respiratory function, VV-ECMO requires large-bore indwelling venous cannulas, which risk bleeding and infections, including endocarditis. Case summary: We describe two adults hospitalized for COVID-19 pneumonia who developed ARDS and right-ventricular failure, requiring VV-ECMO and ProtekDuo cannulation. After over 100 days with these devices, both patients developed tricuspid valve vegetations. Our first patient was decannulated from ECMO and discharged, but re-presented with a segmental pulmonary embolism and tricuspid mass. The Inari FlowTriver system was chosen to percutaneously remove both the tricuspid mass and pulmonary thromboembolism. Pathological examination of the mass demonstrated Candida albicans endocarditis in the setting of Candida fungemia. Our second patient developed a tricuspid valve vegetation which was also removed with the FlowTriever system. Pathological examination demonstrated endocarditis consistent with Pseudomonas aeruginosa in the setting of Pseudomonas bacteremia. Both patients experienced resolution of fungemia and bacteremia after percutaneous vegetation removal. After ECMO decannulation and percutaneous debulking, both patients experienced prolonged hospital stays for ventilator weaning and were eventually discharged with supplemental oxygen. Discussion: VV-ECMO and right-ventricular support devices are invasive and create various risks, including bloodstream infection and infective endocarditis. Percutaneous debulking of valvular vegetations associated with these right-sided indwelling devices may be an effective means of infection source control. It is unclear whether prolonged use of VV-ECMO provides a mortality benefit in COVID-19 ARDS.

Toward reliable calcification detection: calibration of uncertainty in object detection from coronary optical coherence tomography images.

Significance: Optical coherence tomography (OCT) has become increasingly essential in assisting the treatment of coronary artery disease (CAD). However, unidentified calcified regions within a narrowed artery could impair the outcome of the treatment. Fast and objective identification is paramount to automatically procuring accurate readings on calcifications within the artery. Aim: We aim to rapidly identify calcification in coronary OCT images using a bounding box and reduce the prediction bias in automated prediction models. Approach: We first adopt a deep learning-based object detection model to rapidly draw the calcified region from coronary OCT images using a bounding box. We measure the uncertainty of predictions based on the expected calibration errors, thus assessing the certainty level of detection results. To calibrate confidence scores of predictions, we implement dependent logistic calibration using each detection result's confidence and center coordinates. Results: We implemented an object detection module to draw the boundary of the calcified region at a rate of 140 frames per second. With the calibrated confidence score of each prediction, we lower the uncertainty of predictions in calcification detection and eliminate the estimation bias from various object detection methods. The calibrated confidence of prediction results in a confidence error of ∼ 0.13 , suggesting that the confidence calibration on calcification detection could provide a more trustworthy result. Conclusions: Given the rapid detection and effective calibration of the proposed work, we expect that it can assist in clinical evaluation of treating the CAD during the imaging-guided procedure.

Sudden cardiac death in the young: A consensus statement on recommended practices for cardiac examination by pathologists from the Society for Cardiovascular Pathology.

Sudden cardiac death is, by definition, an unexpected, untimely death caused by a cardiac condition in a person with known or unknown heart disease. This major international public health problem accounts for approximately 15-20% of all deaths. Typically more common in older adults with acquired heart disease, SCD also can occur in the young where the cause is more likely to be a genetically transmitted process. As these inherited disease processes can affect multiple family members, it is critical that these deaths are appropriately and thoroughly investigated. Across the United States, SCD cases in those less than 40 years of age will often fall under medical examiner/coroner jurisdiction resulting in scene investigation, review of available medical records and a complete autopsy including toxicological and histological studies. To date, there have not been consistent or uniform guidelines for cardiac examination in these cases. In addition, many medical examiner/coroner offices are understaffed and/or underfunded, both of which may hamper specialized examinations or studies (e.g., molecular testing). Use of such guidelines by pathologists in cases of SCD in decedents aged 1-39 years of age could result in life-saving medical intervention for other family members. These recommendations also may provide support for underfunded offices to argue for the significance of this specialized testing. As cardiac examinations in the setting of SCD in the young fall under ME/C jurisdiction, this consensus paper has been developed with members of the Society of Cardiovascular Pathology working with cardiovascular pathology-trained, practicing forensic pathologists.

Fulminating herpes simplex hepatitis.

Herpes simplex virus (HSV) is a rare cause of acute hepatitis in patients with chronic immunosuppression, including Crohn's disease. HSV hepatitis has the propensity to cause acute liver failure and death. The presenting signs and symptoms can be nonspecific, thereby causing the diagnosis to go overlooked with inadequate management, leading to a high mortality rate. We report a case of a 31-year-old male on chronic prednisone treatment for Crohn's disease who unexpectedly died. Subsequently, an autopsy showed HSV hepatitis as the cause of death. Thus, although a rare complication, HSV hepatitis should always be kept in mind as a fatal complication in patients with acute hepatitis and chronic immunosuppression.

Cardiac and Pulmonary Histopathology in Baboons Following Genetically-Engineered Pig Orthotopic Heart Transplantation.

BACKGROUND Although improving, survival after pig orthotopic heart transplantation (OHTx) in baboons has been mixed and largely poor. The causes for the high incidence of early failure remain uncertain. MATERIAL AND METHODS We have carried out pig OHTx in 4 baboons. Two died or were euthanized within hours, and 2 survived for 3 and 8 months, respectively. There was evidence of a significant 'cytokine storm' in the immediate post-OHTx period with the elevations in IL-6 correlating closely with the final outcome. RESULTS All 4 baboons demonstrated features suggestive of respiratory dysfunction, including increased airway resistance, hypoxia, and tachypnea. Histopathological observations of pulmonary infiltration by neutrophils and, notably, eosinophils within vessels and in the perivascular and peribronchiolar space, with minimal cardiac pathology, suggested a role for early lung acute inflammation. In one, features suggestive of transfusion-related acute lung injury were present. The 2 longer-term survivors died of (i) a cardiac dysrhythmia with cellular infiltration around the conducting tissue (at 3 months), and (ii) mixed cellular and antibody-mediated rejection (at 8 months). CONCLUSIONS These initial findings indicate a potential role of acute lung injury early after OHTx. If this response can be prevented, increased survival may result, providing an opportunity to evaluate the factors affecting long-term survival.

Multi-Scale Reconstruction of Undersampled Spectral-Spatial OCT Data for Coronary Imaging Using Deep Learning.

Coronary artery disease (CAD) is a cardiovascular condition with high morbidity and mortality. Intravascular optical coherence tomography (IVOCT) has been considered as an optimal imagining system for the diagnosis and treatment of CAD. Constrained by Nyquist theorem, dense sampling in IVOCT attains high resolving power to delineate cellular structures/features. There is a trade-off between high spatial resolution and fast scanning rate for coronary imaging. In this paper, we propose a viable spectral-spatial acquisition method that down-scales the sampling process in both spectral and spatial domain while maintaining high quality in image reconstruction. The down-scaling schedule boosts data acquisition speed without any hardware modifications. Additionally, we propose a unified multi-scale reconstruction framework, namely Multiscale-Spectral-Spatial-Magnification Network (MSSMN), to resolve highly down-scaled (compressed) OCT images with flexible magnification factors. We incorporate the proposed methods into Spectral Domain OCT (SD-OCT) imaging of human coronary samples with clinical features such as stent and calcified lesions. Our experimental results demonstrate that spectral-spatial down-scaled data can be better reconstructed than data that are down-scaled solely in either spectral or spatial domain. Moreover, we observe better reconstruction performance using MSSMN than using existing reconstruction methods. Our acquisition method and multi-scale reconstruction framework, in combination, may allow faster SD-OCT inspection with high resolution during coronary intervention.

Giant-cell myocarditis management using short-term TandemHeart support, MANTA closure device, and combination immunosuppression.

We present the case of a 53-year-old woman who presented to the hospital with palpitations and fatigue. The workup revealed new-onset systolic heart failure secondary to giant cell myocarditis. She developed cardiogenic shock, which was managed with the TandemHeart left ventricular assist device and combination immunosuppression strategy. This article highlights our management approach that avoided the need for an urgent heart transplant.

The Genetically Engineered Heart as a Bridge to Allotransplantation in Infants Just Around the Corner?

BACKGROUND: Mortality for infants on the heart transplant waitlist remains unacceptably high, and available mechanical circulatory support is suboptimal. Our goal is to demonstrate the feasibility of utilizing genetically engineered pig (GEP) heart as a bridge to allotransplantation by transplantation of a GEP heart in a baboon. METHODS: Four baboons underwent orthotopic cardiac transplantation from GEP donors. All donor pigs had galactosyl-1,3-galactose knocked out. Two donor pigs had human complement regulatory CD55 transgene and the other 2 had human complement regulatory CD46 and thrombomodulin. Induction immunosuppression included thymoglobulin, and anti-CD20. Maintenance immunosuppression was rapamycin, anti-CD-40, and methylprednisolone. One donor heart was preserved with University of Wisconsin solution and the other three with del Nido solution. RESULTS: All baboons weaned from cardiopulmonary bypass. B217 received a donor heart preserved with University of Wisconsin solution. Ventricular arrhythmias and depressed cardiac function resulted in early death. All recipients of del Nido preserved hearts easily weaned from cardiopulmonary bypass with minimal inotropic support. B15416 and B1917 survived for 90 days and 241 days, respectively. Histopathology in B15416 revealed no significant myocardial rejection but cellular infiltrate around Purkinje fibers. Histopathology in B1917 was consistent with severe rejection. B37367 had uneventful transplant but developed significant respiratory distress with cardiac arrest. CONCLUSIONS: Survival of B15416 and B1917 demonstrates the feasibility of pursuing additional research to document the ability to bridge an infant to cardiac allotransplant with a GEP heart.