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Hybrid ablation combines thoracoscopic epicardial ablation with percutaneous catheter based endocardial ablation for the treatment of AF. The purpose of this study was to evaluate the safety and efficacy of hybrid ablation surgery for the treatment of atrial fibrillation (AF), and to compare outcomes of unilateral vs bilateral thoracoscopic epicardial ablation. Patients with documented AF who underwent hybrid ablation were followed post-operatively for major events. Major events were classified into 2 categories consisting of (1) safety, comprising all-cause mortality and major morbidities, and (2) efficacy, which included recurrence of atrial arrhythmia, cessation of antiarrhythmic drugs (AAD), and completeness of lesion set. A total of 84 consecutive patients were consented for hybrid ablation. Patients presented with an average AF duration of 85.9 months before hybrid ablation. 80 patients underwent successful thoracoscopic epicardial ablation. At 1-year, 87% (60/69) of patients were free from AF and 73% (50/69) were free from AF and off AAD. 63 patients completed both epicardial and endocardial hybrid ablation with posterior wall isolation achieved in 89% (56/63) of patients. Unilateral epicardial ablation was associated with significantly shorter hospital length of stay compared to bilateral surgical approached (3.9 vs 6.7 days, p = 0.002) with no difference in freedom from AF between groups at 1 year. Hybrid ablation for atrial fibrillation is effective for patients at high risk for recurrence after catheter ablation. The unilateral surgical approach may be associated with shorter hospital stay with no appreciable effect on procedure success rates.

Objective Analyze changes in frequency activity and structural organization that occur over time with persistent atrial fibrillation (AF) Background Little is known about the frequency characteristics of the epicardium during transition from paroxysmal to persistent AF. Accurate identification of areas of high dominant frequency (DF) is often hampered by limited spatial resolution. Improvements in electrode arrays provide high spatiotemporal resolution, allowing for characterization of the changes that occur during this transition. Methods AF was induced in adult Yorkshire swine by atrial tachypacing. DF mapping was performed using personalized mapping arrays. Histological analysis and late gadolinium enhanced magnetic resonance imaging were performed to determine structural differences in fibrosis. Results The left atrial epicardium was associated with a significant increase in DF in persistent AF (6.5 ± 0.2 vs. 7.4 ± 0.5 Hz, P = 0.03). The organization index (OI) significantly decreased during persistent AF in both the left atria (0.3 ± 0.03 vs. 0.2 ± 0.03, P = 0.01) and right atria (0.33 ± 0.04 vs. 0.23 ± 0.02, P = 0.02). MRI analysis demonstrated increased ECV values in persistent AF (0.19 vs 0.34, paroxysmal vs persistent, P = 0.05). Tissue sections from the atria showed increase in fibrosis in pigs with persistent AF compared to paroxysmal AF. Staining demonstrated decreased myocardial fiber alignment and loss of anisotropy in persistent AF tissue. Conclusions Changes in tissue organization and fibrosis are observed in the porcine model of persistent AF. Alterations in frequency activity and organization index can be captured with high resolution using flexible electrode arrays.

BACKGROUND: Surgical ablation for atrial fibrillation (AF) can be effective, yet has mixed results. It is unclear which endocardial lesions delivered as part of hybrid therapy‚ will best augment surgical lesion sets in individual patients. We addressed this question by systematically mapping AF endocardially after surgical ablation and relating findings to early recurrence, then performing tailored endocardial ablation as part of hybrid therapy. METHODS: We studied 81 consecutive patients undergoing epicardial surgical ablation (stage 1 hybrid), of whom 64 proceeded to endocardial catheter mapping and ablation (stage 2). Stage 2 comprised high-density mapping of pulmonary vein (PV) or posterior wall (PW) reconnections, low-voltage zones (LVZs), and potential localized AF drivers. We related findings to postsurgical recurrence of AF. RESULTS: Mapping at stage 2 revealed PW isolation reconnection in 59.4%, PV isolation reconnection in 28.1%, and LVZ in 42.2% of patients. Postsurgical recurrence of AF occurred in 36 patients (56.3%), particularly those with long-standing persistent AF ( P =0.017), but had no relationship to reconnection of PVs ( P =0.53) or PW isolation ( P =0.75) when compared with those without postsurgical recurrence of AF. LVZs were more common in patients with postsurgical recurrence of AF ( P =0.002), long-standing persistent AF ( P =0.002), advanced age ( P =0.03), and elevated CHA 2 DS 2 -VASc ( P =0.046). AF mapping revealed 4.4±2.7 localized focal/rotational sites near and also remote from PV or PW reconnection. After ablation at patient-specific targets, arrhythmia freedom at 1 year was 81.0% including and 73.0% excluding previously ineffective antiarrhythmic medications. CONCLUSIONS: After surgical ablation, AF may recur by several modes particularly related to localized mechanisms near low voltage zones, recovery of posterior wall or pulmonary vein isolation, or other sustaining mechanisms. LVZs are more common in patients at high clinical risk for recurrence. Patient-specific targeting of these mechanisms yields excellent long-term outcomes from hybrid ablation.

Newborn mammals, including piglets, exhibit natural heart regeneration after myocardial infarction (MI) on postnatal day 1 (P1), but this ability is lost by postnatal day 7 (P7). The electrophysiologic properties of this naturally regenerated myocardium have not been examined. We hypothesized that epicardial conduction is preserved after P1 MI in piglets. Yorkshire-Landrace piglets underwent left anterior descending coronary artery ligation at age P1 (n = 6) or P7 (n = 7), After 7 weeks, cardiac magnetic resonance imaging was performed with late gadolinium enhancement for analysis of fibrosis. Epicardial conduction mapping was performed using custom 3D-printed high-resolution mapping arrays. Age- and weight-matched healthy pigs served as controls (n = 6). At the study endpoint, left ventricular (LV) ejection fraction was similar for controls and P1 pigs (46.4 ± 3.0% vs. 40.3 ± 4.9%, p = 0.132), but significantly depressed for P7 pigs (30.2 ± 6.6%, p < 0.001 vs. control). The percentage of LV myocardial volume consisting of fibrotic scar was 1.0 ± 0.4% in controls, 9.9 ± 4.4% in P1 pigs (p = 0.002 vs. control), and 17.3 ± 4.6% in P7 pigs (p < 0.001 vs. control, p = 0.007 vs. P1). Isochrone activation maps and apex activation time were similar between controls and P1 pigs (9.4 ± 1.6 vs. 7.8 ± 0.9 ms, p = 0.649), but significantly prolonged in P7 pigs (21.3 ± 5.1 ms, p < 0.001 vs. control, p < 0.001 vs. P1). Conduction velocity was similar between controls and P1 pigs (1.0 ± 0.2 vs. 1.1 ± 0.4 mm/ms, p = 0.852), but slower in P7 pigs (0.7 ± 0.2 mm/ms, p = 0.129 vs. control, p = 0.052 vs. P1). Overall, our data suggest that epicardial conduction dynamics are conserved in the setting of natural heart regeneration in piglets after P1 MI.

Introduction: Spatiotemporal differences in atrial activity are thought to contribute to the maintenance of atrial fibrillation (AF). While recent evidence has identified changes in dominant frequency (DF) during the transition from paroxysmal to persistent AF, little is known about the frequency characteristics of the epicardium during this transition. The purpose of this study was to perform high-resolution mapping of the atrial epicardium and to characterize changes in frequency activity and structural organization during the transition from paroxysmal to persistent AF. Hypothesis: In a porcine model of persistent AF, we tested the hypothesis that the epicardium undergoes spatiotemporal changes in atrial activity and structural organization during persistent AF. Methods: Paroxysmal and persistent AF was induced in adult Yorkshire swine by atrial tachypacing. Atrial morphology was segmented from magnetic resonance imaging and high-resolution patient-specific flexible mapping arrays were 3D printed to match the epicardial contours of the atria. Epicardial activation and DF mapping was performed in four paroxysmal and four persistent AF animals using personalized mapping arrays. Histological analysis was performed to determine structural differences between paroxysmal and persistent AF. Results: The left atrial epicardium was associated with a significant increase in DF between paroxysmal and persistent AF (6.5 ± 0.2 vs. 7.4 ± 0.5 Hz, P = 0.03). High-resolution spatiotemporal mapping identified organized clusters of DF during paroxysmal AF which were lost during persistent AF. The development of persistent AF led to structural remodeling with increased atrial epicardial fibrosis. The organization index (OI) significantly decreased during persistent AF in both the left atria (0.3 ± 0.03 vs. 0.2 ± 0.03, P = 0.01) and right atria (0.33 ± 0.04 vs. 0.23 ± 0.02, P = 0.02). Conclusions: In the porcine model of persistent AF, the epicardium undergoes structural remodeling with increased epicardial fibrosis, reflected by changes in atrial organization index and dominant frequency.

Introduction: The localization of sources responsible for erratic ventricular tachycardia signaling can be facilitated by high-resolution epicardial mapping. Here, we describe an approach for epicardial mapping using 3D printed electrode mapping arrays. We utilize these mapping arrays to perform global beat-to-beat epicardial mapping of ex vivo Langendorff perfused human hearts and demonstrate the ability to identify sources of ventricular tachycardia. Hypothesis: The identification of ventricular tachycardia sources can be facilitated by epicardial mapping with 3D printed flexible mapping arrays. Methods: Epicardial shells were printed using a stereolithography 3D printer using flexible photopolymer resin followed by coupling with custom-designed flexible electrode arrays. Global electroanatomic maps were obtained from Langendorff perfused human hearts during sinus rhythm and after extra stimulus pacing induced ventricular tachycardia. Results: We demonstrate the use of 3D-printed electrode mapping arrays to perform global electroanatomic mapping of the human ventricular epicardium. Flexible 3D printed electrode arrays facilitate high spatial-temporal capture of electrophysiological data in Langendorff perfused human hearts and are capable of identifying epicardial sites of ventricular tachycardia. Conclusions: We report on flexible electrode mapping arrays shaped to match the epicardial contours of the human left and right ventricle. We demonstrate the ability to perform high spatiotemporal resolution mapping of human epicardial signals and demonstrate beat-to-beat global capture of ventricular tachycardia.

Background The surgical maze is suggested to be effective in persistent atrial fibrillation (AF) by reducing the area for fibrillatory wavelets. However, the mechanism for recurrence and next treatment steps are unclear. Purpose We set out to evaluate the impact of complete transmural epicardial maze lesion sets on the extent atrial organization using novel analyses of wide-area recordings of AF. Methods 19 patients (age 50.9±12.0, 78% male) underwent maze followed by endocardial mapping of AF with a 64-pole basket catheter. Block across roof, floor, and pulmonary vein lesions sets was assessed by high-density voltage mapping and organized zones of AF were assessed by panoramic recordings. Total organized area and mean area of the dominant site were evaluated using automated custom scripts. Results Patients had 3.2±0.9 organized regions in 1 minute of LA recordings. A 54 yo F showed residual conduction to the posterior wall from the roof (purple, Fig. 1A) and a figure-of-8 propagation pattern during AF (arrows, fig B) which terminated with localized ablation (yellow lesions, Fig. 1A, red X, Fig. 1B). Overall, patients with complete block on epicardial lesion set had smaller areas of organization (13.7±8% vs. 45.7±32% of mapped areas, p=0.029) vs. those with gaps. The average size of the dominant area was smaller with complete transmural lines than with gaps (5.7±3% vs. 15.9±10%, p=0.033) (Fig. 1C). Conclusion These results show that complete transmural lesion sets constrain the critical mass available for AF, with smaller resulting organized zones. Future studies that quantify how partitioning the atrial surface affects AF may help personalize lesion sets after maze. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NIH NRSA F32 United States

Introduction: Newborn piglets reportedly exhibit natural heart regeneration after myocardial infarction (MI). However, the electrophysiologic properties of this regenerated muscle have not been examined. We hypothesized that epicardial electrical conduction is preserved after MI in newborn piglets. Methods: Yorkshire-Landrace piglets underwent left anterior descending coronary artery ligation on postnatal day 1 (P1, n=4) or postnatal day 7 (P7, n=7), infarcting the anteroseptal left ventricle through which the Purkinje conduction system passes. After 7 weeks, cardiac magnetic resonance imaging (MRI) was performed with late gadolinium enhancement for fibrosis analysis. Epicardial conduction mapping was performed using custom 3D-printed, 256-channel high-resolution mapping arrays (Fig 1A). Age- and weight-matched healthy pigs served as controls (n=7). Data are expressed as mean±SD. Results: MRI analysis revealed significant differences between the control, P1, and P7 groups in ejection fraction (47.6±3.1% vs 37.6±3.3% vs 30.2±6.6%, p Conclusion: P1 piglets exhibited incomplete natural cardiac regeneration after MI but nevertheless demonstrated electrophysiologic conservation of epicardial conduction dynamics.

Purpose Patients undergoing cardiac surgery are at increased risk for heparin-induced thrombocytopenia (HIT). The aim of this study was to identify risk factors and assess the morbidity and mortality associated with HIT in the mechanical circulatory support population. We present a modified “4TMCS” scoring system for this population of patients. MCS represents a “definite” cause of thrombocytopenia and the proposed 4TMCS score replaces the "other causes" category with “Type of mechanical circulatory support”. Methods We performed analysis of patients who underwent cardiac surgery at Stanford University Medical Center between May 1, 2008 and December 31, 2016. Patients were categorized into three groups: 1) Control, patients with normal post-operative platelet count; 2) HIT(-), patients who developed thrombocytopenia and tested negative for HIT; and 3) HIT(+), patients who developed thrombocytopenia and tested positive for HIT. Independent predictors of post-operative HIT were evaluated, and a comparison of diagnostic accuracy between the 4Ts and 4TMCS probability scores was performed. Results We identified 5,314 patients eligible for analysis between 2008 and 2016. In total, 125/5314 (2.4%) patients were diagnosed with HIT, of which 75/5314 (1.4%) had clinical evidence of thrombosis. Overall, in-hospital mortality was 25.6%, 11.7%, and 1.5% in the HIT(+), HIT(-), and control groups, respectively (P Conclusion Heparin-induced thrombocytopenia is associated with worse outcomes and increased morbidity and mortality in patients undergoing cardiac surgery. Patients receiving MCS may be at increased risk for development of post-operative HIT. Awareness of pre-operative patient risk factors and application of a modified 4TMCS probability score may allow for more accurate screening and treatment of HIT in the MCS population.

We describe a design algorithm to build a cardiac myocyte with specific spatial dimensions and physiological function. Using a computational model of a cardiac muscle cell, we modeled calcium (Ca 2+ ) wave dynamics in a cardiac myocyte withcontrolledspatialdimensions.Themodeledmyocytewasreplicatedinvitrowhen primaryneonateratventricularmyocyteswereculturedonmicropatternedsubstrates. The myocytes remodel to conform to the two dimensional boundary conditions and assume the shape of the printed extracellular matrix island. Mechanical perturbation of the myocyte with an atomic force microscope results in calcium-induced calcium release from intracellular stores and the propagation of a Ca 2+ wave, as indicated by high speed video microscopy using fluorescent indicators of intracellular Ca 2+ .A nal- ysis and comparison of the measured wavefront dynamics with those simulated in the computer model reveal that the engineered myocyte behaves as predicted by the model. These results are important because they represent the use of computer mod- eling, computer-aided design, and physiological experiments to design and validate the performance of engineered cells. The ability to successfully engineer biological cells and tissues for assays or therapeutic implants will require design algorithms and tools for quality and regulatory assurance.

Objective: Myocardial infarction resulting from ischemia-reperfusion injury can be reduced by cardiac postconditioning, in which blood flow is restored intermittently prior to full reperfusion. Although key molecular mechanisms and prosurvival pathways involved in postconditioning have been identified, a direct role for eNOS-derived NO in improving regional myocardial perfusion has not been shown. The objective of this study is to measure, with high temporal and spatial resolution, regional myocardial perfusion during ischemia-reperfusion and postconditioning, in order to determine the contribution of regional blood flow effects of NO to infarct size and protection. Methods and Results: We used myocardial contrast echocardiography to measure regional myocardial blood flow in mice over time. Reperfusion after myocardial ischemia-reperfusion injury is improved by postconditioning, as well as by phosphomimetic eNOS modulation. Knock-in mice expressing a phosphomimetic S1176D form of eNOS showed improved myocardial reperfusion and significantly reduced infarct size. eNOS knock-out mice failed to show cardioprotection from postconditioning. The size of the no-reflow zone following ischemia-reperfusion is substantially reduced by postconditioning and by the phosphomimetic eNOS mutation. Conclusions and Significance: Using myocardial contrast echocardiography, we show that temporal dynamics of regional myocardial perfusion restoration contribute to reduced infarct size after postconditioning. eNOS has direct effects on myocardial blood flow following ischemia-reperfusion, with reduction in the size of the no-reflow zone. These results have important implications for ongoing clinical trials on cardioprotection, because the degree of protective benefit may be significantly influenced by the regional hemodynamic effects of eNOS-derived NO., American Heart Association (Predoctoral Fellowship), National Institutes of Health (U.S.) (R01 NS33335), National Institutes of Health (U.S.) (R01 HL57818)

Phosphorylation of endothelial nitric oxide synthase (eNOS) is an important regulator of its enzymatic activity. We generated knockin mice expressing phosphomimetic (SD) and unphosphorylatable (SA) eNOS mutations at S1176 to study the role of eNOS phosphorylation. The single amino acid SA mutation is associated with hypertension and decreased vascular reactivity, while the SD mutation results in increased basal and stimulated endothelial NO production. In addition to these vascular effects, modulation of the S1176 phosphorylation site resulted in unanticipated effects on metabolism. The eNOS SA mutation results in insulin resistance, hyperinsulinemia, adiposity, and increased weight gain on high fat. In contrast, the eNOS SD mutation is associated with decreased insulin levels and resistance to high fat-induced weight gain. These results demonstrate the importance of eNOS in regulation of insulin sensitivity, energy metabolism, and bodyweight regulation, and suggest eNOS phosphorylation as a novel target for the treatment of obesity and insulin resistance.

Changes in myocyte cell shape and tissue structure are concurrent with changes in electromechanical function in both the developing and diseased heart. While the anisotropic architecture of cardiac tissue is known to influence the propagation of the action potential, the influence of tissue architecture and its potential role in regulating excitation–contraction coupling (ECC) are less well defined. We hypothesized that changes in the shape and the orientation of cardiac myocytes induced by spatial arrangement of the extracellular matrix (ECM) affects ECC. To test this hypothesis, we isolated and cultured neonatal rat ventricular cardiac myocytes on various micropatterns of fibronectin where they self-organized into tissues with varying degrees of anisotropy. We then measured the morphological features of these engineered myocardial tissues across several hierarchical dimensions by measuring cellular aspect ratio, myocyte area, nuclear density and the degree of cytoskeletal F-actin alignment. We found that when compared with isotropic tissues, anisotropic tissues have increased cellular aspect ratios, increased nuclear densities, decreased myocyte cell areas and smaller variances in actin alignment. To understand how tissue architecture influences cardiac function, we studied the role of anisotropy on intracellular calcium ([Ca2+]i) dynamics by characterizing the [Ca2+]i–frequency relationship of electrically paced tissues. When compared with isotropic tissues, anisotropic tissues displayed significant differences in [Ca2+]i transients, decreased diastolic baseline [Ca2+]i levels and greater [Ca2+]i influx per cardiac cycle. These results suggest that ECM cues influence tissue structure at cellular and subcellular levels and regulate ECC.

Continuous passive motion (CPM) is currently a part of patient rehabilitation regimens after a variety of orthopedic surgical procedures. While CPM can enhance the joint healing process, the direct effects of CPM on cartilage metabolism remain unknown. Recent in vivo and in vitro observations suggest that mechanical stimuli can regulate articular cartilage metabolism of proteoglycan 4 (PRG4), a putative lubricating and chondroprotective molecule found in synovial fluid and at the articular cartilage surface. ----- ----- Objectives: (1) Determine the topographical variation in intrinsic cartilage PRG4 secretion. (2) Apply a CPM device to whole joints in bioreactors and assess effects of CPM on PRG4 biosynthesis.----- ----- Methods: A bioreactor was developed to apply CPM to bovine stifle joints in vitro. Effects of 24 h of CPM on PRG4 biosynthesis were determined.----- ----- Results: PRG4 secretion rate varied markedly over the joint surface. Rehabilitative joint motion applied in the form of CPM regulated PRG4 biosynthesis, in a manner dependent on the duty cycle of cartilage sliding against opposing tissues. Specifically, in certain regions of the femoral condyle that were continuously or intermittently sliding against meniscus and tibial cartilage during CPM, chondrocyte PRG4 synthesis was higher with CPM than without.----- ----- Conclusions: Rehabilitative joint motion, applied in the form of CPM, stimulates chondrocyte PRG4 metabolism. The stimulation of PRG4 synthesis is one mechanism by which CPM may benefit cartilage and joint health in post-operative rehabilitation. (C) 2006 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.