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Delivery of comprehensive arrhythmia care requires the simultaneous presence of many resources. These include complex hospital infrastructure, expensive implantable equipment, and expert personnel. In many low- and middle-income countries (LMICs), at least 1 of these components is often missing, resulting in a gap between the demand for arrhythmia care and the capacity to supply care. In addition to this treatment gap, there exists a training gap, as many clinicians in LMICs have limited access to formal training in cardiac electrophysiology. Given the progressive increase in the burden of cardiovascular diseases in LMICs, these patient care and clinical training gaps will widen unless further actions are taken to build capacity. Several strategies for building arrhythmia care capacity in LMICs have been described. Medical missions can provide donations of both equipment and clinical expertise but are only intermittently present and therefore are not optimized to provide the longitudinal support needed to create self-sustaining infrastructure. Use of donated or reprocessed equipment (eg, cardiac implantable electronic devices) can reduce procedural costs but does not address the need for infrastructure, including diagnostics and expert personnel. Collaborative efforts involving multiple stakeholders (eg, professional organizations, government agencies, hospitals, and educational institutions) have the potential to provide longitudinal support of both patient care and clinician education in LMICs.

Left atrial appendage closure (LAAC) is an important strategy to reduce stroke risk in patients with non-valvular atrial fibrillation (AF) who are at high risk of bleeding on long-term anticoagulation. Real-world assessments of the safety of the Watchman LAAC device remain limited. The objective of this study was to determine the frequency and timing of adverse events associated with Watchman LAAC device implants performed after FDA approval. Adverse events associated with Watchman LAAC implants performed between March 2015 and March 2019 were identified through a search of the FDA Manufacturer and User Facility Device Experience (MAUDE) database. During the study period, 3,652 unique adverse events were identified. An estimated 43,802 Watchman implants were performed in the United States during the study period. The overall adverse event rate was 7.3% and the mortality rate was 0.4%. Of the 159 unique types of adverse events identified, pericardial effusion was most common (1.4%). Most adverse events (73%) occurred intraoperatively (59%) or within 1 day of the procedure (15%). However, 19% of deaths, 24% of strokes and 27% of device embolizations occurred >1 month after implantation. The rates of most Watchman-related adverse events reported in the MAUDE database were comparable to those observed in clinical trials. A majority of adverse events occurred within 1 day of implant. In conclusion, while the absolute event rates were low, a significant proportion of device embolizations, strokes, and deaths occurred >1 month after Watchman implant.

Background Lyme carditis, defined as direct infection of cardiac tissue by Borrelia bacteria, affects up to 10% of patients with Lyme disease. The most frequently reported clinical manifestation of Lyme carditis is cardiac conduction system disease. The goal of this study was to identify the incidence and predictors of permanent pacemaker implantation in patients hospitalized with Lyme disease. Methods A retrospective cohort analysis of the Nationwide Inpatient sample was performed to identify patients hospitalized with Lyme disease in the US between 2003 and 2014. Patients with Lyme carditis were defined as those hospitalized with Lyme disease who also had cardiac conduction disease, acute myocarditis, or acute pericarditis. Patients who already had pacemaker implants at the time of hospitalization (N = 310) were excluded from the Lyme carditis subgroup. The primary study outcome was permanent pacemaker implantation. Secondary outcomes included temporary cardiac pacing, permanent pacemaker implant, and in-hospital mortality. Results Of the 96,140 patients hospitalized with Lyme disease during the study period, 10,465 (11%) presented with Lyme carditis. Cardiac conduction system disease was present in 9,729 (93%) of patients with Lyme carditis. Permanent pacemaker implantation was performed in 1,033 patients (1% of all Lyme hospitalizations and 11% of patients with Lyme carditis-associated conduction system disease). Predictors of permanent pacemaker implantation included older age (OR: 1.06 per 1 year; 95% CI:1.05–1.07; P Conclusions Approximately 11% of patients hospitalized with Lyme disease present with carditis, primarily in the form of cardiac conduction system disease. In this 12-year study, 1% of all hospitalized patients and 11% of those with Lyme-associated cardiac conduction system disease underwent permanent pacemaker implantation.

Background Cardiovascular events in the context of COVID-19 infection increase the risk of negative patient outcomes, but large cohort studies describing this association are limited. The purpose of the current study was to investigate the potential associations between cardiovascular events and mortality in patients hospitalized due to COVID-19. Methods A retrospective chart review was performed in 2450 patients hospitalized for confirmed COVID-19 infection within a single hospital network between March 15 and June 15, 2020. Logistic regression analysis was used to identify predictors of mortality. Results In the study population, 57% of patients had elevated high sensitivity troponin (hs-TnT) levels. Acute heart failure occurred in 23% of patients and arrhythmias were observed in 8% of patients. Of the 1401 patients with elevated hs-TnT levels, a primary cardiac etiology (e.g., myocardial infarction) was identified in 653 (47%) patients. In the remaining 748 (53%) patients, there was evidence of a primary non-cardiac etiology for hs-TnT elevation such as renal failure (n = 304) and critical illness (n = 286). Elevated hs-TnT was associated with increased risk of mortality. A significantly higher mortality rate was observed for hs-TnT elevation associated with a primary cardiac etiology (OR 4.6, 95% CI: 2.7–7.6; P

Purpose of review Atrial fibrillation (AF) is the most common arrhythmia in adults and is responsible for 600,000 emergency department (ED) visits each year in the USA. Over 60% of these patients are admitted to inpatient units. The prevalence of AF is increasing, resulting in higher numbers of AF-related ED visits and inpatient admissions. These trends underscore the need for improvements in the efficiency of AF management in the ED. Recent findings Several treatment protocols have been developed to address challenges associated with AF management in the ED, including: initiation of oral anticoagulant (OAC) therapy, cardioversion, and arranging for outpatient follow-up. Studies of these protocols have demonstrated that they can be utilized safely and effectively. Published treatment protocols for AF in the ED have been shown to reduce unnecessary hospital admissions and improve adherence to guideline-directed OAC therapy. Widespread adoption of AF treatment protocols could improve patient outcomes and reduce the costs associated with inpatient AF treatment.

Introduction: Acute myocarditis is a serious complication of influenza. While current reports suggest that subclinical cardiac involvement may be transient, myocarditis has been implicated in up to a third of sudden deaths in patients with influenza. Methods: Patients hospitalized with influenza in the US between 2003 and 2017 were identified using the Nationwide Inpatients Sample. They were subsequently classified to specify those with and without a diagnosis of myocarditis and specific outcomes of interest were compared between these subgroups. Results: : Between 2003 and 2017, 1,187,615 patients were hospitalized with influenza in the US. Of these, 2,430 patients (0.2%) were diagnosed with myocarditis while 1,185,185 patients (99.8%) did not have myocarditis. Patient characteristics and outcomes are shown in the table below. Independent predictors of myocarditis were: age (adjusted odds ratio [aOR]:0.98; 95% CI:0.98-0.99), male sex (aOR:1.21 ; 95% CI:1.01-1.46), Elixhauser score ≥3 (aOR:1.34; 95% CI:1.07-1.7), coagulopathy (aOR:1.67; 95% CI:1.29-2.17), valvular disease (aOR:1.5; 95% CI:1.07-2.1), abnormal weight loss (aOR:1.7; 95% CI:1.23-2.35), and a diagnosis of the 2009 H1N1 influenza virus (aOR:4.79; 95% CI:1.51-15.24). Independent predictors of death in patients hospitalized with influenza myocarditis were: age (aOR:1.04; 95% CI:1.01-1.06), stroke (aOR:11.16; 95% CI:1.57-79.49), shock (aOR:61.1; 95% CI:11.88-314.3), renal failure (aOR:3.56; 95% CI:1.2 -10.55), coagulopathy (aOR:2.62; 95% CI:1.04-6.6), and electrolyte disorders (aOR:3.19; 95% CI:1.07-9.47). Conclusions: Patients with influenza who develop myocarditis are younger than those without myocarditis and have more interventions, longer LOS and worse outcomes including a four-fold higher risk of cardiac arrest and a two-fold higher mortality rate. The strongest independent predictor of developing myocarditis was having the 2009 H1N1 influenza virus infection.

Background Delivery of hydrogels to the heart is a promising strategy for mitigating the detrimental impact of myocardial infarction ( MI ). Challenges associated with the in vivo delivery of currently available hydrogels have limited clinical translation of this technology. Gelatin methacryloyl (Gel MA ) bioadhesive hydrogel could address many of the limitations of available hydrogels. The goal of this proof‐of‐concept study was to evaluate the cardioprotective potential of Gel MA in a mouse model of MI . Methods and Results The physical properties of Gel MA bioadhesive hydrogel were optimized in vitro. Impact of Gel MA bioadhesive hydrogel on post‐ MI recovery was then assessed in vivo. In 20 mice, Gel MA bioadhesive hydrogel was applied to the epicardial surface of the heart at the time of experimental MI . An additional 20 mice underwent MI but received no Gel MA bioadhesive hydrogel. Survival rates were compared for Gel MA ‐treated and untreated mice. Left ventricular function was assessed 3 weeks after experimental MI with transthoracic echocardiography. Left ventricular scar burden was measured with postmortem morphometric analysis. Survival rates at 3 weeks post‐ MI were 89% for Gel MA ‐treated mice and 50% for untreated mice ( P =0.011). Left ventricular contractile function was better in Gel MA ‐treated than untreated mice (fractional shortening 37% versus 26%, P MA ‐treated mice was lower than in untreated mice (6% versus 22%, P =0.017). Conclusions Epicardial Gel MA bioadhesive application at the time of experimental MI was performed safely and was associated with significantly improved post‐ MI survival compared with control animals. In addition, Gel MA treatment was associated with significantly better preservation of left ventricular function and reduced scar burden.

Purpose We have recently reported a method for measuring rest-stress myocardial blood flow (MBF) using a single, relatively short, PET scan session. The method requires two IV tracer injections, one to initiate rest imaging and one at peak stress. We previously validated absolute flow quantitation in ml/min/cc for standard bull's eye, segmental analysis. In this work, we extend the method for fast computation of rest-stress MBF parametric images. Methods We provide an analytic solution to the single-scan rest-stress flow model which is then solved using a two-dimensional table lookup method (LM). Simulations were performed to compare the accuracy and precision of the lookup method with the original non-linear method (NLM). Then the method was applied to 16 single scan rest/stress measurements made in 12 pigs: 7 studied after infarction of the left anterior descending artery (LAD) territory, and 9 imaged in the native state. Parametric maps of rest and stress MBF as well as maps of left (fLV) and right (fRV) ventricular spill-over fractions were generated. Regions of interest (ROIs) for 17 myocardial segments were defined in bull's eye fashion on the parametric maps. The mean of each ROI was then compared to the rest (K1r) and stress (K1s) MBF estimates obtained from fitting the 17 regional TACs with the NLM. Results In simulation, the LM performed as well as the NLM in terms of precision and accuracy. The simulation did not show that bias was introduced by the use of a predefined two-dimensional lookup table. In experimental data, parametric maps demonstrated good statistical quality and the LM was computationally much more efficient than the original NLM. Very good agreement was obtained between the mean MBF calculated on the parametric maps for each of the 17 ROIs and the regional MBF values estimated by the NLM (K1map LM=1.019 x K1ROI NLM + 0.019, R2=0.986; mean difference= 0.034 ± 0.036 mL/min/cc). Conclusions: We developed a table lookup method for fast computation of parametric imaging of rest and stress MBF. Our results show the feasibility of obtaining good quality MBF maps using modest computational ressources, thus demonstrating that the method can be applied in a clinical environment to obtain full quantitative MBF information. This article is protected by copyright. All rights reserved.

18F-labeled myocardial flow agents are becoming available for clinical application but the ∼2 hour half-life of 18F complicates their clinical application for rest-stress measurements. The goal of this work is to evaluate in a pig model a single-scan method which provides quantitative rest-stress blood flow in less than 15 minutes. Single-scan rest-stress measurements were made using 18F-Flurpiridaz. Nine scans were performed in healthy pigs and seven scans were performed in injured pigs. A two-injection, single-scan protocol was used in which an adenosine infusion was started 4 minutes after the first injection of 18F-Flurpiridaz and followed either 3 or 6 minutes later by a second radiotracer injection. In two pigs, microsphere flow measurements were made at rest and during stress. Dynamic images were reoriented into the short axis view, and regions of interest (ROIs) for the 17 myocardial segments were defined in bull’s eye fashion. PET data were fitted with MGH2, a kinetic model with time varying kinetic parameters, in which blood flow changes abruptly with the introduction of adenosine. Rest and stress myocardial blood flow (MBF) were estimated simultaneously. The first 12–14 minutes of rest-stress PET data were fitted in detail by the MGH2 model, yielding MBF measurement with a mean precision of 0.035 ml/min/cc. Mean myocardial blood flow across pigs was 0.61 ± 0.11 mL/min/cc at rest and 1.06 ± 0.19 mL/min/cc at stress in healthy pigs and 0.36 ± 0.20 mL/min/cc at rest and 0.62 ± 0.24 mL/min/cc at stress in the ischemic area. Good agreement was obtained with microsphere flow measurement (slope = 1.061 ± 0.017, intercept = 0.051 ± 0.017, mean difference 0.096 ± 0.18 ml/min/cc). Accurate rest and stress blood flow estimation can be obtained in less than 15 min of PET acquisition. The method is practical and easy to implement suggesting the possibility of clinical translation.

Background Real-time radiofrequency (RF) ablation lesion assessment is a major unmet need in cardiac electrophysiology. Objective The purpose of this study was to assess whether improved temperature measurement using a novel thermocoupling (TC) technology combined with information derived from impedance change, contact force (CF) sensing, and catheter orientation allows accurate real-time prediction of ablation lesion formation. Methods RF ablation lesions were delivered in the ventricles of 15 swine using a novel externally irrigated-tip catheter containing 6 miniature TC sensors in addition to force sensing technology. Ablation duration, power, irrigation rate, impedance drop, CF, and temperature from each sensor were recorded. The catheter "orientation factor" was calculated using measurements from the different TC sensors. Information derived from all the sources was included in a mathematical model developed to predict lesion depth and validated against histologic measurements. Results A total of 143 ablation lesions were delivered to the left ventricle (n = 74) and right ventricle (n = 69). Mean CF applied during the ablations was 14.34 ± 3.55g, and mean impedance drop achieved during the ablations was 17.5 ± 6.41 Ω. Mean difference between predicted and measured ablation lesion depth was 0.72 ± 0.56 mm. In the majority of lesions (91.6%), the difference between estimated and measured depth was ≤1.5 mm. Conclusion Accurate real-time prediction of RF lesion depth is feasible using a novel ablation catheter-based system in conjunction with a mathematical prediction model, combining elaborate temperature measurements with information derived from catheter orientation, CF sensing, impedance change, and additional ablation parameters.

Background Variability in the management of atrial fibrillation ( AF ) in the emergency department ( ED ) leads to avoidable hospital admissions and prolonged length of stay ( LOS ). In a retrospective single‐center study, a multidisciplinary AF treatment pathway was associated with a reduced hospital admission rate and reduced LOS . To assess the applicability of the AF pathway across institutions, we conducted a 2‐center study. Methods and Results We performed a prospective, 2‐stage study at 2 tertiary care hospitals. During the first stage, AF patients in the ED received routine care. During the second stage, AF patients received care according to the AF pathway. The primary study outcome was hospital admission rate. Secondary outcomes included ED LOS and inpatient LOS . We enrolled 104 consecutive patients in each stage. Patients treated using the AF pathway were admitted to the hospital less frequently than patients who received routine care (15% versus 55%; P LOS was shorter in the AF pathway cohort than in the routine care cohort (64 versus 105 hours, respectively; P =0.01). There was no significant difference in the average ED LOS between AF pathway and routine care cohorts (14 versus 12 hours, respectively; P =0.32). Conclusions In this prospective 2‐stage, 2‐center study, utilization of a multidisciplinary AF treatment pathway resulted in a 3.7‐fold reduction in admission rate and a 1.6‐fold reduction in average hospital LOS for admitted patients. Utilization of the AF pathway was not associated with a significant change in ED LOS .

Although susceptibility to cardiovascular disease (CVD) is different for every patient, why some patients with type 2 diabetes mellitus (T2DM) develop CVD while others are protected has not yet been clarified. Using T2DM-patient-derived human induced pluripotent stem cells (hiPSCs), we found that in patients protected from CVD, there was significantly elevated expression of an esterase, arylacetamide deacetylase (AADAC), in vascular smooth muscle cells (VSMCs). We overexpressed this esterase in human primary VSMCs and VSMCs differentiated from hiPSCs and observed that the number of lipid droplets was significantly diminished. Further metabolomic analyses revealed a marked reduction in storage lipids and an increase in membrane phospholipids, suggesting changes in the Kennedy pathway of lipid bioassembly. Cell migration and proliferation were also significantly decreased in AADAC-overexpressing VSMCs. Moreover, apolipoprotein E (Apoe)-knockout mice overexpressing VSMC-specific Aadac showed amelioration of atherosclerotic lesions. Our findings suggest that higher AADAC expression in VSMCs protects T2DM patients from CVD.

A Man with Atrial Fibrillation, Depression, and Anxiety A 62-year-old man with a history of major depressive disorder and generalized anxiety disorder was evaluated in the psychiatry clinic because...

Bioprinting has emerged as a promising tool in tissue engineering and regenerative medicine. Various three dimensional (3D) printing strategies have been developed to enable bioprinting of various biopolymers and hydrogels. However, the incorporation of biological factors has not been well explored. As the importance of personalized medicine is becoming more clear, the need for the development of bioinks containing autologous/patient-specific biological factors for tissue engineering applications becomes more evident. We used platelet-rich plasma (PRP) as a patient-specific rich source of autologous growth factors that can be easily incorporated to hydrogels and printed into 3D constructs. PRP contains a cocktail of growth factors enhancing angiogenesis, stem cell recruitment and tissue regeneration. Here, we report the development of an alginate-based bioink that can be printed and crosslinked upon implantation through exposure to native calcium ions. This platform can be used for the controlled release of PRP-associated growth factors which may ultimately enhance vascularization and stem cell migration.

BACKGROUND Mitochondrial membrane potential (ΔΨm) arises from normal function of the electron transport chain. Maintenance of ΔΨm within a narrow range is essential for mitochondrial function. Methods for in vivo measurement of ΔΨm do not exist. We use 18F-labeled tetraphenylphosphonium (18F-TPP+) to measure and map the total membrane potential, ΔΨT, as the sum of ΔΨm and cellular (ΔΨc) electrical potentials. METHODS Eight pigs, five controls and three with a scar-like injury, were studied. Pigs were studied with a dynamic PET scanning protocol to measure 18F-TPP+ volume of distribution, VT. Fractional extracellular space (fECS) was measured in 3 pigs. We derived equations expressing ΔΨT as a function of VT and the volume-fractions of mitochondria and fECS. Seventeen segment polar maps and parametric images of ΔΨT were calculated in millivolts (mV). RESULTS In controls, mean segmental ΔΨT = -129.4±1.4 mV (SEM). In pigs with segmental tissue injury, ΔΨT was clearly separated from control segments but variable, in the range -100 to 0 mV. The quality of ΔΨT maps was excellent, with low noise and good resolution. Measurements of ΔΨT in the left ventricle of pigs agree with previous in in-vitro measurements. CONCLUSIONS We have analyzed the factors affecting the uptake of voltage sensing tracers and developed a minimally invasive method for mapping ΔΨT in left ventricular myocardium of pigs. ΔΨT is computed in absolute units, allowing for visual and statistical comparison of individual values with normative data. These studies demonstrate the first in vivo application of quantitative mapping of total tissue membrane potential, ΔΨT.

A 71-year-old man presented with sudden chest pain, diaphoresis, shortness of breath, and hypotension. An electrocardiogram showed new ST-segment elevations. Ten days earlier, an implantable cardioverter–defibrillator had been placed. Diagnostic procedures were performed.

Balloon catheter-based techniques that apply mechanical force to blood vessel walls have dramatically advanced the standard of care for patients with vascular disease. But balloons are limited in their therapeutic potential because they rely on mechanics alone and lack electronically active materials. Recent advances in balloon catheters with integrated electrodes have offered additional treatment capabilities through the application of both mechanical contact force and radio frequency electromotive force. However, these smart balloons remain limited in their mechanics and their ability to provide diagnostic information about local vessel hemodynamics and tissue health near treatment zones. Here, we demonstrate a novel instrumented balloon catheter system that contains stretchable electrodes and thermal-based blood flow sensors, providing hemodynamic information, electrical stimulation, and ablation therapy on a single device. This system accommodates high inflation pressure (∼2 atm) and twisting and bending over a broad range of vascular diameters and geometries. Finite element and analytical modeling capture the anisotropic mechanical and thermal properties of the device during cycles of inflation and deflation in a simulated biological environment. Bench-top ablation and in vivo blood flow measurements highlight the utility of this technology for clinical application.

Background Transcatheter aortic valve replacement (TAVR) has emerged as an alternative treatment for patients with symptomatic aortic stenosis who are at high risk for surgical aortic valve replacement. The development of conduction abnormalities is a major complication in the postprocedural period of TAVR. Objectives The objective of this study was to investigate the development of postprocedural conduction abnormalities and the requirement of permanent pacemaker (PPM) implantation in patients undergoing TAVR. Methods Data from 137 consecutive patients who underwent TAVR (Edwards SAPIEN valve, Edwards Lifesciences, Irvine, CA, USA) between June 2008 and October 2012 were reviewed. Patients with prior history of PPM (n = 27) were excluded. The role of various predictors for pacemaker implantation after TAVR, including the valve index (calculated as [valve size/left ventricular outflow tract diameter] × 100) was investigated. Results A total of 31/110 (28.2%) patients required implantation of a PPM after TAVR. The median time to implantation of a PPM was 5 days after the procedure. The development of postprocedural complete heart block was the most common indication for implantation of a PPM (16/31; 51.6%). On multivariate analysis, the presence of preexisting right bundle branch block (RBBB) was found to be a strong predictor of PPM implantation after TAVR (adjusted odds ratio: 4.87; 95% confidence interval: 1.29–18.46, P = 0.020). Using the receiver operated curve analysis, a cut-off value of valve index of 128 was found to be a strong predictor for PPM implantation with a sensitivity of 73% and specificity of 61% (c statistic = 0.68). Conclusions This study identified the presence of prior RBBB and a valve index of 128 as important risk factors for PPM implantation after TAVR. A larger implanted valve size relative to left ventricular outflow tract diameter leads to a greater compression of the intrinsic conduction system, increasing the need for pacemaker placement.

Established classes of high-performance electronics have driven advances in interventional biomedicine. However, the large size, planar geometry and stiff mechanical properties of standard conventional electronics employed in medical devices give rise to important integration challenges with soft biological tissue. Stretchable and flexible biointegrated electronics could improve treatment procedures across a broad range of applications, including cardiac, neural and endovascular therapies. Here we present novel mechanics, materials and integration strategies for this new class of bioelectronics onboard minimally invasive catheter based systems. Co-located arrays of sensors and actuators affixed to cardiac and angioplasty balloon catheters capture new sensory information during ablation procedures, offering physicians the ability to adjust placement and treatment intra-procedurally. New circuit topologies, enabled by stretchable electronics, also overcome long standing challenges associated with transmitting vast amounts of data through narrow catheter lumens, thus allowing for a large number of sensors to be multiplexed for mapping electrophysiological activity with high spatiotemporal resolution and with a minimal number of routing wires. We present representative examples that highlight the clinical significance of soft bio-integrated electronics, along with the mechanics and processes that enable this technology.

Aims Delivery of high-power short-duration radiofrequency (RF) ablation lesions is not commonly used, in part because conventional thermocouple (TC) technology underestimates tissue temperature, increasing the risk of steam pop, and thrombus formation. We aimed to test whether utilization of an ablation catheter equipped with a highly accurate novel TC technology could facilitate safe and effective delivery of high-power RF lesions. Methods and results Adult male Yorkshire swine were used for the study. High-power short-duration ablations (10-s total; 90 W for 4 s followed by 50 W for 6 s) were delivered using an irrigated force sensing catheter, equipped with six miniature TC sensors embedded in the tip electrode shell. Power modulation was automatically performed when the temperature reached 65°C. Ablation parameters were recorded and histopathological analysis was performed to assess lesion formation. One hundred and fourteen RF applications, delivered using the study ablation protocol in the ventricles of eight swine [53 in the right ventricle (RV), 61 in the left ventricle (LV)], were analysed. Average power delivered was 55.4 ± 5.3 W and none of the ablations resulted in a steam pop. Fourteen out of the 114 (12.3%) lesions were transmural. The mean lesion depth was 3.9 ± 1.1 mm for the 100 non-transmural lesions. Similar ablation parameters resulted in bigger impedance drop (11.6 Ω vs. 9.1 Ω, P = 0.009) and deeper lesions in the LV compared with the RV (4.3 ± 1.2 mm vs. 3.3 ± 0.8 mm, P

Background Magnetic resonance imaging (MRI) has been considered contraindicated in patients with cardiac pacemakers (PPMs). Recently, Medtronic (MDT) MRI SureScan PPM (Medtronic Inc., Minneapolis, MN, USA) and leads were introduced into clinical practice in the United States of America. Objective To compare MDT CapSureFix 5086 MRI SureScan lead-associated perforation and dislodgement rates with MDT non-MRI SureScan active fixation leads. Methods We retrospectively analyzed the records of all patients implanted with MDT CapSureFix 5086 MRI SureScan leads as well as all patients implanted with MDT 4076 and 5076 leads at our institution from April 2011 to April 2014. Results Four of 72 patients implanted with MDT CapSureFix 5086 MRI SureScan leads (5.5%) had evidence of lead perforation, necessitating pericardiocentesis in three cases and lead revision in one case. Three of the four perforations were delayed perforations, presenting more than 3 weeks postimplant. Two patients implanted with MDT CapSureFix 5086 MRI SureScan leads (2.8%) had lead dislodgement. Of 420 patients implanted with MDT non-MRI SureScan leads, there were two perforations (0.47%) and four dislodgements (0.9%). There were significantly increased lead perforations associated with MDT CapSureFix 5086 MRI SureScan leads (P = 0.005) and a nonsignificant trend toward increased dislodgements (P = 0.18) when compared with MDT non-MRI SureScan leads. Conclusion In contradiction to prior studies, this retrospective study suggests an increased perforation rate with MDT CapSureFix 5086 MRI SureScan leads. Most perforations were delayed perforations, presenting more than 3 weeks postimplant. Higher volume prospective studies with longer follow-up are needed to confirm our findings.

Single-scan rest-stress measurements were made usingThe first 12-14 minutes of rest-stress PET data were fitted in detail by the MGH2 model, yielding MBF measurement with a mean precision of 0.035 ml/min/cc. Mean myocardial blood flow across pigs was 0.61 ± 0.11 mL/min/cc at rest and 1.06 ± 0.19 mL/min/cc at stress in healthy pigs and 0.36 ± 0.20 mL/min/cc at rest and 0.62 ± 0.24 mL/min/cc at stress in the ischemic area. Good agreement was obtained with microsphere flow measurement (slope = 1.061 ± 0.017, intercept = 0.051 ± 0.017, mean difference 0.096 ± 0.18 ml/min/cc).Accurate rest and stress blood flow estimation can be obtained in less than 15 min of PET acquisition. The method is practical and easy to implement suggesting the possibility of clinical translation.

Conventional electroanatomical mapping systems employ roving catheters with one or a small number of electrodes. Maps acquired using these systems usually contain a small number of points and take a long time to acquire. Use of a multielectrode catheter could facilitate rapid acquisition of higher-resolution maps through simultaneous collection of data from multiple points in space; however, a large multielectrode array could potentially limit catheter maneuverability. The purpose of this study was to test the feasibility of using a novel, multielectrode catheter to map the right atrium and the left ventricle. Electroanatomical mapping of the right atrium and the left ventricle during both sinus and paced rhythm were performed in five swine using a conventional mapping catheter and a novel, multielectrode catheter. Average map acquisition times for the multielectrode catheter (with continuous data collection) ranged from 5.2 to 9.5 min. These maps contained an average of 2,753 to 3,566 points. Manual data collection with the multielectrode catheter was less rapid (average map completion in 11.4 to 18.1 min with an average of 870 to 1,038 points per map), but the conventional catheter was slower still (average map completion in 28.6 to 32.2 min with an average 120 to 148 points per map). Use of this multielectrode catheter is feasible for mapping the left ventricle as well as the right atrium. The multielectrode catheter facilitates acquisition of electroanatomical data more rapidly than a conventional mapping catheter. This results in shorter map acquisition times and higher-density electroanatomical maps in these chambers.

Summary Development of regenerative therapeutic strategies to reverse the progression of advanced heart failure is one of the most urgent clinical needs of this century. Insights gained from clinical trials of adult stem cells, together with fundamental scientific advances in cardiac stem cell and regenerative biology, are beginning to yield potential new targets and strategies for regenerative therapies. Of particular importance are new scientific discoveries related to intrinsic cardiac regeneration, renewal factors that can trigger regeneration, and tissue-engineering technology, which are beginning to change the way investigators view the scientific and clinical position of cardiovascular regenerative therapy.

Introduction The 12-lead surface electrocardiogram (ECG) is commonly used as a noninvasive modality to assess for left atrial enlargement (LAE), but data comparing ECG against cardiac computed tomography (CT) for LAE is lacking. We aimed to determine the diagnostic performance of 6 ECG criteria for LAE as compared with CT left atrial volume (LAV) and index to body surface area (LAVI) as the reference standard. Materials and Methods In 339 patients (age: mean ± mean, 53 ± 12 years; 63% male), we evaluated the quantitative ECG parameters of P duration, P to PR segment ratio, P wave area, and P terminal force in lead V1. We also assessed qualitatively the morphology of bifid and biphasic P waves. Patients were stratified into top and lowest quartile of LAV and LAVI by CT. Results Of the 6 ECG criteria, patients with P duration greater than 110 milliseconds had a 2½-fold increase likelihood of being in the top quartile of LAV (adjusted odds ratio [OR], 2.51; P = .01) and LAVI (adjusted OR, 2.74; P = .007) as measured by CT. For this ECG criterion, the sensitivity and specificity were 71% and 55% for CT LAE by LAV and 61% and 55% for LAVI. The remaining ECG parameters of LAE assessed (P to PR segment ratio, P terminal force in lead V1, P wave area, bifid, and biphasic P wave) were not associated with LAE by CT-based LAV or LAVI (all P ≥ .20). Discussion Only P duration greater than 110 milliseconds was independently associated with LAE based on CT-derived LA volume and index. However, none of the established ECG parameters of LAE have sufficient diagnostic accuracies for predicting volumetric enlargement by CT, thus limiting its clinical utility.

Objective Cardiac computed tomography (CT) is a state-of-the-art technology that provides an accurate noninvasive method to quantify left ventricular mass for analysis of left ventricular hypertrophy (LVH). We aimed to examine seven ECG-based LVH criteria against two CT indexation criteria for LVH: a CT-specific body surface area cutoff and the obesity-independent height criteria. Methods In 333 patients (mean age 53 +/- 12 years, 61% men), 64-slice contrast-enhanced CT was performed and 12-lead surface ECG within 24 h. Left ventricular mass was measured at end-diastole. Using both CT indexation criteria, the cohort was subdivided into patients with LVH and without LVH. The seven ECG criteria for LVH were the Cornell voltage index, Cornell voltage duration product, Cornell/strain index, Sokolow-Lyon index, Romhilt-Estes scores at least 4 and at least 5, and Gubner-Ungerleider. Results The ECG parameters had high specificities (85-97%) and variable low sensitivities (4-43%) when compared to either CT criteria of LVH. The three Cornell-based methods performed the best (test-positive likelihood ratio: 4.5-6.7), followed by the Sokolow-Lyon and Romhilt-Estes scores (test-positive likelihood ratio: 2.3-4.0). With the exception of the Gubner-Ungerleider criterion, the other six ECG criteria were associated with at least one of the CT-based LVH (adjusted odds ratio 2.4-9.5) and had incremental predictive value beyond that of hypertension history. Conclusion Using cardiac CT as a gold standard for LVH assessment, ECG criteria for LVH have high specificities with the three Cornell-based criteria providing the best test performance for identifying patients with LVH.

Much of the information on evolution of gene regulatory networks (GRN) was generated from studies in invertebrates (Erwin and Davidson 2009). Comparison of fungi species revealed evolution of GRNs at both cis and trans levels (Scannell and Wolfe 2004). Invertebrate GRNs can be “rewired” at the “cis” level through changes in genomic regions that regulate gene transcription, or cis-regulatory modules (CRM). CRM can gain or lose transcription factor (TF) binding sites (TFBSs) by single nucleotide mutations, insertions and deletions of neutral sequence or TFBSs (Erwin and Davidson 2009). It has been argued that at the cis level, the transcription regulatory apparatus is a “programmable” computing machine whose function can be modulated through placements of TFBSs in the regulatory region of any gene (Buchler et al. 2003; Gertz et al. 2009). A notable advantage of encoding combinatorial control in the regulatory region, as opposed to in the regulatory proteins, is evolvability (Ptashne and Gann 2002): Unlike regulatory proteins, each cis-regulatory region controls the expression of a given gene and hence can be programmed with minimal pleiotropic effects. Contrary to this argument, changes to the TF that are produced by the cell (“trans” changes) appear to be widely tolerated by Escherichia coli and may even confer evolutionary advantages (Isalan et al. 2008). Moreover, several yeast species implement compensating cis and trans changes to achieve a conserved regulatory logic (Tsong et al. 2006). This study attempted to add vertebrate data to address these arguments by analyzing a relatively conserved developmental process in three mammalian species. Mammalian preimplantation embryonic development (PED) encompasses the period from fertilization to implantation of the embryo in the endometrial lining of the uterus. Just after fertilization, the transcriptome of the embryo is comprised of maternally deposited transcripts. After several cell divisions, maternal transcripts are specifically degraded and are replaced by zygotic transcripts produced by the new diploid nucleus containing both maternal and paternal genes. This transition is termed zygote genome activation (ZGA). The timing of ZGA and maternal transcript degradation varies among species, but in humans and bovines it reportedly occurs between the four- and eight-cell stages of development, while in mouse, this transition occurs between the one- and two-cell stages of development, consistent with an overall accelerated pace of murine embryonic development (Braude et al. 1988; Kanka et al. 2003; Adjaye et al. 2007; Kues et al. 2008). Another major event during PED is the differentiation and specialization of cells. Immediately after ZGA, embryos undergo compaction, a process during which dividing embryonic cells become a tightly organized cell mass with an indistinguishable membrane. In most mammalian embryos, compaction is usually observed between the eight- and 16-cell stages. After compaction, the embryo is named the morula, which becomes the blastocyst through formation of an internal cavity and further cellular differentiation. At least two cell types can be distinguished in the blastocyst: an inner cell mass (ICM) and an outer layer of cells termed the trophectoderm. The ICM contributes to all three germ layers present in the mature adult (known as pluripotency). Embryonic stem (ES) cells were derived from ICM, and ES cells have been used as surrogates to analyze the molecular mechanisms in ICM and preimplantation embryos (Ogawa et al. 2008). The progression of PED is highly conserved among mammals: All progress through the same morphologic stages. Perhaps the most marked difference is the amount of time spent at each stage. The other notable interspecies differences appear after the blastocyst stage, including that bovine blastocysts initiate the gastrulation process before implantation, and the formation and functions of the placenta and yolk sac (Gossler 1992). In this study, we chose the highly conserved PED stages, i.e., from zygote to blastocyst stages for cross-species GRN comparison.

Management of atrial fibrillation (AF) in the emergency department (ED) is variable because of the absence of universally adopted treatment guidelines. To address potentially preventable hospital admissions and prolonged length of stay, an AF treatment pathway was co-developed by physicians from the cardiac electrophysiology service and the department of emergency medicine at our institution. The impact of this AF pathway on patient outcomes was evaluated with a prospective, observational study conducted in a single tertiary care center from July 1, 2013, to June 30, 2014. The primary study outcome was the rate of hospital admission. The secondary outcomes were duration of ED visit and inpatient length of stay. The 94 patients treated according to the AF pathway during the study period were less likely to be admitted than the 265 patients who received routine care (16% vs 80%, p0.001). For admitted patients, the mean length of stay was shorter for patients treated according to the AF pathway (32 vs 85 hours, p = 0.002). The time spent in the ED was longer for patients in the AF pathway (16 vs 85 hours, p0.001). Utilization of a multidisciplinary pathway for management of AF in the ED led to a significant reduction in the rate of hospital admission. Patients who were admitted after receiving care according to the AF pathway had a shorter length of stay. In conclusion, utilization of a multidisciplinary AF pathway resulted in a 5-fold reduction in admission rate and2-fold reduction length of stay for admitted patients.

The RAG1 and RAG2 proteins together constitute the nuclease that initiates the assembly of immunoglobulin and T cell receptor genes in a reaction known as V(D)J recombination. RAG1 plays a central role in recognition of the recombination signal sequence (RSS) by the RAG1/2 complex. To investigate the parameters governing the RAG1-RSS interaction, the murine core RAG1 protein (amino acids 377-1008) fused to a short Strep tag has been purified to homogeneity from bacteria. The Strep-RAG1 (StrRAG1) protein exists as a dimer at a wide range of protein concentrations (25-500 nM) in the absence of DNA and binds with reasonably high affinity and specificity (apparent K(D) = 41 nM) to the RSS. Both electrophoretic mobility shift assays and polarization anisotropy experiments indicate that only a single StrRAG1-DNA species exists in solution. Anisotropy decay measured by frequency domain spectroscopy suggests that the complex contains a dimer of StrRAG1 bound to a single DNA molecule. Using measurements of protein intrinsic fluorescence and circular dichroism, we demonstrate that StrRAG1 undergoes a major conformational change upon binding the RSS. Steady-state fluorescence and acrylamide quenching studies reveal that this conformational change is associated with a repositioning of intrinsic protein fluorophores from a hydrophobic to a solvent-exposed environment. RSS-induced conformational changes of StrRAG1 may influence the interaction of RAG1 with RAG2 and synaptic complex formation.

Transcatheter aortic valve replacement (TAVR) has emerged as an alternative treatment for surgical high-risk patients with severe aortic stenosis. The aim of this study was to determine the impact of atrial fibrillation (AF) on procedural outcomes. Data from 137 patients who underwent TAVR using Edwards SAPIEN valve were reviewed. The predictors of new-onset atrial fibrillation (NOAF) after the procedure were analyzed. In addition, the post-TAVR clinical outcomes and adverse events were compared according to the presence and absence of preprocedural and postprocedural AF. Previous AF was present in 49% of the patients who underwent TAVR. After the procedure, NOAF was detected in 21% of patients, and the cumulative incidence of post-TAVR AF was 60%. After TAVR, 50% of all the episodes of NOAF occurred in the initial 24 hours after the procedure. Transapical approach was observed to an important predictor of NOAF (adjusted odds ratio [OR] 5.05, 95% confidence interval [CI] 1.40 to 18.20, p = 0.013). The composite outcome of all-cause mortality, stroke, vascular complications, and repeat hospitalization in 1 month after TAVR was significantly higher in patients with previous AF (33 of 67 vs 19 of 70, adjusted OR 2.60, 95% CI 1.22 to 5.54, p = 0.013) compared with patients who did not have previous AF. The presence of post-TAVR AF led to a prolongation in the duration of intensive care unit stay by an average of 70 hours (95% CI 25 to 114.7 hours, p = 0.002). Similarly, post-TAVR AF also led to the prolongation in the hospital stay by an average of 6.7 days (95% CI 4.69 to 8.73 days, p0.0005). In conclusion, our study demonstrates that the presence of AF before TAVR is an important predictor of the composite end point of all-cause mortality, stroke, vascular complications, and repeat hospitalization in 1 month after the procedure. AF after TAVR is more likely to be encountered with the transapical approach and is associated with a prolongation of intensive care unit and hospital stay.

Magnetic resonance imaging (MRI) has been considered contraindicated in patients with cardiac pacemakers (PPMs). Recently, Medtronic (MDT) MRI SureScan PPM (Medtronic Inc., Minneapolis, MN, USA) and leads were introduced into clinical practice in the United States of America.To compare MDT CapSureFix 5086 MRI SureScan lead-associated perforation and dislodgement rates with MDT non-MRI SureScan active fixation leads.We retrospectively analyzed the records of all patients implanted with MDT CapSureFix 5086 MRI SureScan leads as well as all patients implanted with MDT 4076 and 5076 leads at our institution from April 2011 to April 2014.Four of 72 patients implanted with MDT CapSureFix 5086 MRI SureScan leads (5.5%) had evidence of lead perforation, necessitating pericardiocentesis in three cases and lead revision in one case. Three of the four perforations were delayed perforations, presenting more than 3 weeks postimplant. Two patients implanted with MDT CapSureFix 5086 MRI SureScan leads (2.8%) had lead dislodgement. Of 420 patients implanted with MDT non-MRI SureScan leads, there were two perforations (0.47%) and four dislodgements (0.9%). There were significantly increased lead perforations associated with MDT CapSureFix 5086 MRI SureScan leads (P = 0.005) and a nonsignificant trend toward increased dislodgements (P = 0.18) when compared with MDT non-MRI SureScan leads.In contradiction to prior studies, this retrospective study suggests an increased perforation rate with MDT CapSureFix 5086 MRI SureScan leads. Most perforations were delayed perforations, presenting more than 3 weeks postimplant. Higher volume prospective studies with longer follow-up are needed to confirm our findings.

V(D)J recombination is instigated by the recombination-activating proteins RAG1 and RAG2, which catalyze site-specific DNA cleavage at the border of the recombination signal sequence (RSS). Although both proteins are required for activity, core RAG1 (the catalytically active region containing residues 384-1008 of 1040) alone displays binding specificity for the conserved heptamer and nonamer sequences of the RSS. The nonamer-binding region lies near the N terminus of core RAG1, whereas the heptamer-binding region has not been identified. Here, potential domains within core RAG1 were identified using limited proteolysis studies. An iterative procedure of DNA cloning, protein expression, and characterization revealed the presence of two topologically independent domains within core RAG1, referred to as the central domain (residues 528-760) and the C-terminal domain (residues 761-980). The domains do not include the nonamer-binding region but rather largely span the remaining relatively uncharacterized region of core RAG1. Characterization of macromolecular interactions revealed that the central domain bound to the RSS with specificity for the heptamer and contained the predominant binding site for RAG2. The C-terminal domain bound DNA cooperatively but did not show specificity for either conserved RSS element. This domain was also found to self-associate, implicating it as a dimerization domain within RAG1.

The V(D)J recombination reaction is composed of multiple nucleolytic processing steps mediated by the recombination-activating proteins RAG1 and RAG2. Sequence analysis has suggested that RAG2 contains six kelch repeat motifs that are predicted to form a six-bladed beta-propeller structure, with the second beta-strand of each repeat demonstrating marked conservation both within and between kelch repeat-containing proteins. Here we demonstrate that mutations G95R and DeltaI273 within the predicted second beta-strand of repeats 2 and 5 of RAG2 lead to immunodeficiency in patients P1 and P2. Green fluorescent protein fusions with the mutant proteins reveal appropriate localization to the nucleus. However, both mutations reduce the capacity of RAG2 to interact with RAG1 and block recombination signal cleavage, therefore implicating a defect in the early steps of the recombination reaction as the basis of the clinical phenotype. The present experiments, performed with an extensive panel of site-directed mutations within each of the six kelch motifs, further support the critical role of both hydrophobic and glycine-rich regions within the second beta-strand for RAG1-RAG2 interaction and recombination signal recognition and cleavage. In contrast, multiple mutations within the variable-loop regions of the kelch repeats had either mild or no effects on RAG1-RAG2 interaction and hence on the ability to mediate recombination. In all, the data demonstrate a critical role of the RAG2 kelch repeats for V(D)J recombination and highlight the importance of the conserved elements of the kelch motif.

Two recent papers outline improvements in gene editing technology that may facilitate the analysis of signaling networks important for development. The systems developed by both Thyagarajan and coworkers (Thyagarajan et al., 2007) in Nature Biotechnology, and Lombardo and colleagues (Lombardo et al., 2007) in Stem Cells, have the potential to advance our understanding of human embryonic stem cells.

In a cell-free approach to regenerative therapeutics, transient application of paracrine factors in vivo could be used to alter the behavior and fate of progenitor cells to achieve sustained clinical benefits. Here we show that intramyocardial injection of synthetic modified RNA (modRNA) encoding human vascular endothelial growth factor-A (VEGF-A) results in the expansion and directed differentiation of endogenous heart progenitors in a mouse myocardial infarction model. VEGF-A modRNA markedly improved heart function and enhanced long-term survival of recipients. This improvement was in part due to mobilization of epicardial progenitor cells and redirection of their differentiation toward cardiovascular cell types. Direct in vivo comparison with DNA vectors and temporal control with VEGF inhibitors revealed the greatly increased efficacy of pulse-like delivery of VEGF-A. Our results suggest that modRNA is a versatile approach for expressing paracrine factors as cell fate switches to control progenitor cell fate and thereby enhance long-term organ repair.

The ability to achieve transmural, durable ablation lesions is a significant challenge of a pulmonary veins isolation (PVI) procedure resulting in their reconnection. We aim to assess the effect of utilization of a force-sense irrigated tip catheters in conjunction with a novel automated ablation

Background The delivery of radiofrequency (RF) energy to the posterior left atrium creates a risk of injury to the adjacent esophagus. Esophageal endoscopy (EGD) is used to screen patients at risk for esophageal thermal injury after RF ablation. Objective The purpose of this study was to analyze the macroscopic features of the severity of esophageal injuries induced by RF ablation to the left atrium as seen by EGD and evaluate the association of these descriptions with the time elapsed until complete healing. Methods This study analyzed 219 patients undergoing RF ablation for atrial fibrillation. Esophageal temperature probes were used during each ablation, and EGD was performed in cases with intraesophageal temperature ≥39°C. Repeat EGD was obtained at 10 days to evaluate for healing in all cases demonstrating esophageal injury. Serial endoscopies were repeated every 2 weeks until complete healing was documented. Lesions were classified according to severity as superficial or deep ulceration; size and shape were also noted. Results We found 37.4% of patients (82 of 219) with esophageal intraluminal temperatures ≥39°C. Of these, 22 patients (27%) were identified with esophageal injury, with 68% being superficial ulcerations and 32% deep. On repeat EGD at 10 days, only 29% of deep ulcerations were healed, as compared with 87% of the superficial injuries (P = .0136). No difference in healing was found when analyzed for size or shape. Conclusions The macroscopic severity of esophageal lesions detected on endoscopy the day after RF ablation can predict the time to resolution, with severe, deep ulcerations requiring a longer time to heal.