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Background: Left atrial appendage occlusion (LAAO) has historically been performed using intraprocedural transesophageal echocardiography (TEE) and fluoroscopy. Multiple recent reports have described the feasibility and advantages of utilizing two-dimensional intracardiac echocardiography (ICE) for LAAO. However, in inexperienced hands, safe manipulation of the ICE catheter in the left atrium (LA) can be challenging. Objective: To assess the feasibility and efficacy of three-dimensional (3D) ICE mapping in guiding LAAO device implant compared to standard TEE imaging. Methods: We retrospectively included patients who underwent LAAO in our institution from January 2017 and October 2021. We compared baseline demographics, intraprocedural data, post-procedural complications, and outcomes. P= value of

Introduction: VT is often refractory to medical therapy and on rare but critical cases, even EP ablation. Despite investigation into endocardial, mesocardial and occasionally even epicardial ablation for these recalcitrant and deadly arrhythmias, there remains an inability to more effectively, non-invasively, treat VT. Hypothesis: We propose that, paralleling a Gamma Knife ® approach, the use of a novel MRI linear accelerator (MR Linac), the Unity ® (Elekta AB, Stockholm, Sweden), a proof of concept could be applied to highly selected pts with obstinate VT. Methods: A multi-center team with EP, Radiation Oncology and CMR (GE 1.5T) in joint development with Pittsburgh, PA and Utrecht, The Netherlands, developed a completely EP-CMR-guided method for non-invasive VT ablation utilizing S tereo T actic A rrhythmia R adioablation (STAR) with 25 Gy in a single fraction via MR Linac. Results: To evaluate deliverability and applicability of MR Linac plans, four IMRT per clinical scan were developed with varying delivery parameters (7A: 7-beams: 52 o in 70 segments (seg), 7B: 7-beams: 52 o in 100 seg, 15A: 15-beams: 24 o in 70 seg, and 15B: 15-beams: 24 o in 100 seg). We used a 0.2 cm dose grid and a 1% uncertainty via Monte Carlo ® dose calculation. Pt specific QA/QC used ArcCHECK ® (Sun Nuclear, FL) to evaluate individual IMRT plans. 3D CMR with LGE scar fusion for lesion integration guided non-invasive MR LinAc ablation. Accordingly, all IMRT plans were clinically acceptable (>97% of 7-beams and ≥98.0% of 15-beams in 3%/3mm gamma) for MR LinAc VT-ablation successfully with pt target effective arrhythmogenic myocardial ROI volume as ascertained via CMR of 63-99cm 3 . All 4 pts tolerated the 25±5min procedure without esophageal, pericardial or pro-arrhythmic complications and were alive at 30d FU with marked attenuation of VT burden. At 30d FU, no SAE's occurred to include pro-arrhythmias, pericardial effusions or esophageal fistulas. Conclusions: Refractory, complex and anatomically endocardially-remote VT has the potential to be curative, incorporating an analogous Gamma Knife ® approach via MR Linac radioablation heralding a migration to the Unity ® platform. This nearly first-in-man p r oof of concept approach may shepherd a new methodologic era into heretofore intractable VT.

Introduction Atrial fibrillation (AF) ablation requires access to the left atrium (LA) via transseptal puncture (TP). TP is traditionally performed with fluoroscopic guidance. Use of intracardiac echocardiography (ICE) and three-dimensional mapping allows for zero fluoroscopy TP. Objective To demonstrate safety and efficacy of zero fluoroscopy TP using multiple procedural approaches. Methods Patients undergoing AF ablation between January 2015 and November 2017 at five institutions were included. ICE and three-dimensional mapping were used for sheath positioning and TP. Variable technical approaches were used across centers including placement of J wire in the superior vena cava with ICE guidance followed by dragging down the transseptal sheath into the interatrial septum, or guiding the transseptal sheath directly to the interatrial septum by localizing the ablation catheter with three-dimensional mapping and replacing it with the transseptal needle once in position. In patients with pacemaker/implantable cardiac defibrillator leads, pre-/poststudy device interrogation was performed. Results A total of 747 TPs were performed (646 patients, age 63.1 ± 13.1, 67.5% male, LA volume index 34.5 ± 15.8 mL/m2 , ejection fraction 57.7 ± 10.9%) with 100% success. No punctures required fluoroscopy. Two pericardial effusions, two pericardial tamponades requiring pericardiocentesis, and one transient ischemic attack were observed during the overall ablation procedure, with a total complication rate of 0.7%. There were no other periprocedural complications related to TP, including intrathoracic bleeding, stroke, or death both immediately following TP and within 30 days of the procedure. In patients with intracardiac devices, no device-related complications were observed. Conclusion TP can be safely and effectively performed without the need for fluoroscopy.

Background— Recognition of myocardial ischemia is critical both for the diagnosis of coronary artery disease and the selection and evaluation of therapy. Recent advances in proteomic and metabolic profiling technologies may offer the possibility of identifying novel biomarkers and pathways activated in myocardial ischemia. Methods and Results— Blood samples were obtained before and after exercise stress testing from 36 patients, 18 of whom demonstrated inducible ischemia (cases) and 18 of whom did not (controls). Plasma was fractionated by liquid chromatography, and profiling of analytes was performed with a high-sensitivity electrospray triple-quadrupole mass spectrometer under selected reaction monitoring conditions. Lactic acid and metabolites involved in skeletal muscle AMP catabolism increased after exercise in both cases and controls. In contrast, there was significant discordant regulation of multiple metabolites that either increased or decreased in cases but remained unchanged in controls. Functional pathway trend analysis with the use of novel software revealed that 6 members of the citric acid pathway were among the 23 most changed metabolites in cases (adjusted P =0.04). Furthermore, changes in 6 metabolites, including citric acid, differentiated cases from controls with a high degree of accuracy ( P c -statistic=0.83). Conclusions— We report the novel application of metabolomics to acute myocardial ischemia, in which we identified novel biomarkers of ischemia, and from pathway trend analysis, coordinate changes in groups of functionally related metabolites.

Background— It is known that 5-lipoxygenase and its product, leukotriene B4 (LTB 4 ), are highly expressed in several human pathologies, including atherosclerotic plaque. LTB 4 signals primarily through its high-affinity G protein-coupled receptor BLT1, which is expressed on specific leukocyte subsets. BLT1 receptor expression and function on other atheroma-associated cell types is unknown. Methods and Results— To directly assess the role of the LTB 4 -BLT1 pathway in atherogenesis, we bred BLT1 −/− mice into the atherosclerosis-susceptible apoE −/− strain. Compound-deficient apoE −/− /Blt1 −/− mice fed a Western-type diet had a marked reduction in plaque formation compared with apoE −/− controls. Immunohistochemical analysis of atherosclerotic lesions in compound-deficient mice revealed a striking decrease in smooth muscle cells (SMCs) and significant decreases in macrophages and T cells. We report here novel evidence of the expression and function of BLT1 on vascular SMCs. LTB 4 triggered SMC chemotaxis, which was pertussis toxin sensitive in Blt1 +/+ SMCs and absent in Blt1 −/− cells, suggesting that BLT1 was the dominant receptor mediating effector functions through a G protein-coupled signaling pathway. Furthermore, BLT1 colocalized with SMCs in human atherosclerotic lesions. Conclusions— These new findings extend the role of inducible BLT1 to nonleukocyte populations and suggest an important target for intervention to modulate the response to vascular injury.

Integrin-linked kinase (ILK) is a phosphoinositide 3-kinase-dependent serine/threonine kinase that interacts with beta integrins. Here we show that endothelial cell (EC)-specific deletion of ILK in mice confers placental insufficiency with decreased labyrinthine vascularization, yielding no viable offspring. Deletion of ILK in zebra fish using antisense morpholino oligonucleotides results in marked patterning abnormalities of the vasculature and is similarly lethal. To dissect potential mechanisms responsible for these phenotypes, we performed ex vivo deletion of ILK from purified EC of adult mice. We observed downregulation of the active-conformation of beta1 integrins with a striking increase in EC apoptosis associated with activation of caspase 9. There was also reduced phosphorylation of the ILK kinase substrate, Akt. However, phenotypic rescue of ILK-deficient EC by wild-type ILK, but not by a constitutively active mutant of Akt, suggests regulation of EC survival by ILK in an Akt-independent manner. Thus, endothelial ILK plays a critical role in vascular development through integrin-matrix interactions and EC survival. These data have important implications for both physiological and pathological angiogenesis.

Increasing implantable cardioverter-defibrillator (ICD) use in response to broad indications in recent years has heightened the need to better refine selection for patients most likely to benefit. Although no single test adequately predicts sudden cardiac death risk, it seems intuitive that the best markers should be those that directly reflect electric instability and abnormalities of the underlying myocardial substrate. The advanced recording capacity of ICDs allows detailed investigation of spontaneous ventricular tachycardia (VT) episodes that would previously have been inaccessible and to potentially aid in documenting characteristics of clinically significant VTs. Different VTs occurring in the same patient can vary in stability, duration, and hemodynamic consequence. The ability to document and monitor for certain distinguishing features might provide new insights into the underlying pathophysiology and thus help to inform assessments of risk. Although ICDs discriminate between VTs primarily based on differences in rate, stored electrograms (EGMs) also have been used to help identify the arrhythmia origin and in a recent study, to help discriminate likely regions of origin for different “clinical” VTs while pace mapping in patients postinfarction.1 Article see p 33 In this issue of Circulation: Arrhythmia and Electrophysiology , Hadid et al2 analyze stored EGMs to evaluate the incidence and predictive value of pleomorphic VT and multiple VT morphologies among patients enrolled in the DATAS (Dual Chamber and Atrial Tachyarrhythmias Adverse Events Study) trial,3 in which ICDs were implanted under standard class I indications according to the 1998 American College of Cardiology/American Heart Association guidelines, as well as for MUSTT (Multicenter Unsustained Tachycardia Trial) criteria after November 2001. This study is the first to use ICD EGMs to systematically study pleomorphic VT, which was defined as a single VT episode having >1 stable ICD EGM morphology, each lasting at least 6 consecutive beats. The incidence …

Air pollution episodes have been associated with increased cardiovascular hospital admissions and mortality in time-series studies. We tested the hypothesis that patients with implanted cardioverter defibrillators experience potentially life-threatening arrhythmias after such air pollution episodes. We compared defibrillator discharge interventions among 100 patients with such devices in eastern Massachusetts, according to variations in concentrations of particulate matter, black carbon, and gaseous air pollutants that were measured daily for the years 1995 through 1997. A 26-ppb increase in nitrogen dioxide was associated with increased defibrillator interventions 2 days later (odds ratio = 1.8; 95% confidence interval = 1.1-2.9). Patients with ten or more interventions experienced increased arrhythmias in association with nitrogen dioxide, carbon monoxide, black carbon, and fine particle mass. These results suggest that elevated levels air pollutants are associated with potentially life-threatening arrhythmia leading to therapeutic interventions by an implanted cardioverter defibrillator.

Emerging metabolomic tools have created the opportunity to establish metabolic signatures of myocardial injury. We applied a mass spectrometry–based metabolite profiling platform to 36 patients undergoing alco-hol septal ablation treatment for hypertrophic obstructive cardiomyopathy, a human model of planned myo-cardial infarction (PMI). Serial blood samples were obtained before and at various intervals after PMI, with patients undergoing elective diagnostic coronary angiography and patients with spontaneous myocardial infarction (SMI) serving as negative and positive controls, respectively. We identified changes in circulating levels of metabolites participating in pyrimidine metabolism, the tricarboxylic acid cycle and its upstream con-tributors, and the pentose phosphate pathway. Alterations in levels of multiple metabolites were detected as early as 10 minutes after PMI in an initial derivation group and were validated in a second, independent group of PMI patients. A PMI-derived metabolic signature consisting of aconitic acid, hypoxanthine, trimethylamine N-oxide, and threonine differentiated patients with SMI from those undergoing diagnostic coronary angiogra-phy with high accuracy, and coronary sinus sampling distinguished cardiac-derived from peripheral metabolic changes. Our results identify a role for metabolic profiling in the early detection of myocardial injury and sug-gest that similar approaches may be used for detection or prediction of other disease states.

Background— Studies to define the overall contribution of lymphocytes to lesion formation in atherosclerosis-susceptible mice have demonstrated relatively subtle effects; the use of lymphocyte-deficient mice, however, compromises both the effector and regulatory arms of the immune system. Here, we tested the hypothesis that deletion of CXCL10 (IP-10), a chemokine specific for effector T cells that has been localized within atherosclerotic lesions, would significantly inhibit atherogenesis. Methods and Results— Compound deficient Apoe −/− / Cxcl10 −/− mice fed a Western-style diet for either 6 or 12 weeks demonstrated significant reductions in atherogenesis as compared with Apoe −/− controls, as assessed by both aortic en face and cross-sectional analyses. Immunohistochemical studies revealed a decrease in the accumulation of CD4 + T cells, whereas quantitative polymerase chain reaction analysis of lesion-rich aortic arches demonstrated a marked reduction in mRNA for CXCR3, the CXCL10 chemokine receptor. Although overall T-cell accumulation was diminished significantly, we found evidence to suggest that regulatory T-cell (T reg ) numbers and activity were enhanced, as assessed by increased message for the T reg -specific marker Foxp3, as well as increases in immunostaining for the T reg -associated cytokines interleukin-10 and transforming growth factor-β1. We also documented naturally occurring T reg cells in human atherosclerotic lesions. Conclusions— We provide novel evidence for a functional role for the effector T-cell chemoattractant CXCL10 in atherosclerotic lesion formation by modulating the local balance of the effector and regulatory arms of the immune system.

Early disease detection often relies on accurate measurement of serum or plasma biomarkers. Available tests for myocardial infarction, such as immuonoassays for the troponins, developed out of studies of those proteins in cardiac physiology. Advancements in protein display and identification technologies now permit characterization of global alterations associated with disease conditions. Plasma proteomics in particular, through an unbiased survey of all proteins associated with a given cardiovascular pathology, may lead to the discovery of novel biomarkers and may provide insight into the cellular mechanisms of disease and uncover new proteins that might serve as targets for therapeutic intervention. Advancing instrumentation and computational methodologies are allowing not only exploration but also quantification of the proteomes of biological tissues and fluids on a wide scale. However, there remains lack of consensus and standardization in technology and techniques. Choice of sample is sometimes not obvious; there is not just one proteome, but many. Faster automation, coupled with more accurate mass determinations, more reliable protein databases to accelerate protein identifications, and greater software support, is needed to realize the true potential of proteomics. Finally, the high sensitivity of mass spectrometry and the present lack of bioinformatics standardization make it critical that any suspected proteomic changes be thoroughly reviewed and verified, with the focus on addressing any inadvertent biases or artifacts of collection, handling, storage, or analysis.

Integrin-linked kinase (ILK) is a serine/threonine kinase that is important in cell-matrix interactions and cell signaling. To examine the role of ILK in leukocyte trafficking and survival, we generated T cell-specific ILK knockouts by breeding ILK(flox/flox) mice to transgenic mice expressing Cre recombinase under control of the Lck proximal promoter. Thymic T cells from Lck-Cre(+)/ILK(flox/flox) mice had a marked reduction (>95%) in ILK protein levels. Thymic cellularity was comparable in 3- to 4-week-old mice, but a threefold diminution of thymic T cells became evident by 6 to 8 weeks of age in the T cell-specific ILK knockout mice due to increased cell death of double-positive (DP) T cells. Analysis of peripheral T cells by quantitative PCR and by breeding Lck-Cre(+)/ILK(flox/flox) mice to a YFP-transgenic reporter strain demonstrated an approximate 20-fold enrichment of ILK-competent cells, suggesting these cells have a competitive advantage in trafficking to and/or survival in peripheral lymphatic organs. We explored mechanisms related to altered cell trafficking and survival that might explain the decreases in thymic cellularity and enrichment for ILK-competent cells in the spleen and lymph nodes. We observed a >50% reduction in chemotaxis of ILK-deficient T cells to the chemokines CXCL12 (stromal cell-derived factor [SDF]-1alpha) and CCL19 (macrophage inflammatory protein [MIP]-3beta), as well as enhanced apoptosis of ILK-deficient cells upon stress. Signaling studies in ILK-deficient T cells demonstrated diminished phosphorylation of Akt on the activating phosphorylation site, Ser 473, and a concordant decrease in Akt kinase activity following stimulation with the chemokine SDF-1. Rac1 activation was also markedly diminished in ILK-deficient T cells following chemokine stimulation. These data extend the role of ILK to immune-cell trafficking and survival via modulation of Akt- and Rac-dependent substrates, and have implications for cell recruitment in both homeostatic and pathological processes.

Objective—Leukotriene B4(LTB4) has been implicated in the trafficking of monocytes to inflammatory pathologic conditions, such as transplant rejection and atherosclerosis. The aim of this study was to determine the mechanisms by which LTB4contributes to monocyte capture from the circulation.Methods and Results—In in vitro and in vivo vascular models, the lipid chemoattractant LTB4was an equipotent agonist of monocyte adhesion compared with the chemokine monocyte chemoattractant protein-1 (MCP-1). Adenoviral gene transfer of specific endothelial adhesion molecules and blocking monoclonal antibody studies demonstrated that LTB4triggers both β1- and β2-integrin–dependent adhesion. Flow cytometry studies suggested that changes in integrin avidity or affinity, rather than alterations of integrin surface expression, were responsible for the chemoattractant-triggered arrest. Surprisingly, in contrast to the peptide chemokine MCP-1, LTB4did not activate the phosphoinositide 3-kinase pathway, which is a functionally critical step in chemokine-triggered effector functions.Conclusions—LTB4is a potent trigger of monocyte adhesion under flow yet mediates its effects via pathways that appear to differ from peptide chemoattractants. A better understanding of the mechanisms of LTB4-induced monocyte trafficking might shed insight into disease pathogenesis and pinpoint critical steps for therapeutic intervention for multiple human inflammatory pathologic conditions.

The closed chest convergent procedure is a multidisciplinary approach to atrial fibrillation (AF) treatment. Epicardial posterior left atrial (PLA) ablation is performed by a cardiac surgeon using a transdiaphragmatic endoscope, immediately followed by percutaneous pulmonary vein (PV) isolation performed by a cardiac electrophysiologist. Interim outcomes for the treatment of non-paroxysmal AF (NPAF) were evaluated based on peri-procedural safety and complications, freedom from recurrent AF, and need for cardioversion or repeat catheter ablation at three, six and 12 months post-procedure. A total of 43 patients (86 % NPAF) underwent the convergent procedure. Patients were 84 % male, with mean age 58.6 ± 8.7 years. Mean AF duration was 45.4 ± 40.3 months. Pre-procedure left atrium (LA) volumetric data using cardiac magnetic resonance imaging (MRI) or computed tomography (CT) was available for 30 patients (70 %). Average LA volume was 155.5 ± 48.4 millilitres (ml); two-thirds of patients had a LA volume >130 ml. There was no operative or peri-operative mortality. Sinus rhythm (SR) was recorded at three months in 31 of 39 (79 %) patients, at six months in 24 of 27 (89 %) patients and at 12 months in nine patients. The convergent procedure is a safe and effective option for both PV isolation and PLA substrate ablation in NPAF patients. Long-term follow-up is required and randomised clinical trials warranted.

There has been an increased interest in applying deep neural networks to automatically interpret and analyze the 12-lead electrocardiogram (ECG). The current paradigms with machine learning methods are often limited by the amount of labeled data. This phenomenon is particularly problematic for clinically-relevant data, where labeling at scale can be time-consuming and costly in terms of the specialized expertise and human effort required. Moreover, deep learning classifiers may be vulnerable to adversarial examples and perturbations, which could have catastrophic consequences, for example, when applied in the context of medical treatment, clinical trials, or insurance claims. In this paper, we propose a physiologically-inspired data augmentation method to improve performance and increase the robustness of heart disease detection based on ECG signals. We obtain augmented samples by perturbing the data distribution towards other classes along the geodesic in Wasserstein space. To better utilize domain-specific knowledge, we design a ground metric that recognizes the difference between ECG signals based on physiologically determined features. Learning from 12-lead ECG signals, our model is able to distinguish five categories of cardiac conditions. Our results demonstrate improvements in accuracy and robustness, reflecting the effectiveness of our data augmentation method., 26 pages, Figure 13, Machine Learning for Healthcare 2022