Citations

Determining whether retrograde ventriculoatrial (VA) conduction is through the AV node (AVN) or an accessory pathway (AP) is critical for successful ablation of supraventricular tachycardia (SVT). With introduction of ventricular extrastimuli (VEST), retrograde right bundle branch block (retro RBBB) may occur and result in abrupt VH interval prolongation. We hypothesized when retrograde conduction is via an AP, VA interval change is less than VH interval change, whereas with retrograde AVN conduction, VA interval change is equal to or greater than VH interval change. We retrospectively reviewed the electrophysiology (EP) studies of patients undergoing ablation for AVNRT (n=55) or AVRT (n=50). The intracardiac electrograms were reviewed for induction of retro RBBB and change in VH and VA intervals during VEST. Parahisian pacing, decremental pacing, arrhythmia diagnosis and ablation outcomes were reviewed. All results were found to be reproducible between two independent observers with inter and intra observer reliability scores of 1.00 for identification of retro RBBB and greater than 0.85 for measurement of VH and VA intervals. Of 105 patients, 84 (80%) had evidence of induced retro RBBB during VEST. The average VH interval increase with induction of retro RBBB was 53.7 ms for patients with retrograde AP conduction and 54.4 ms for patients with AVN conduction (p=ns). The average VA interval increase with induction of retro RBBB was 13.6 ms with AP conduction and 70.1 ms with AVN conduction (P < 0.001). All patients with a greater VH than VA interval change had a final diagnosis of AVRT and those with a VH change less than VA change had AVNRT, yielding sensitivity and specificity of 100%. Using a cutoff of 50 ms for change in VA interval with onset of retro RBBB to diagnose AVNRT accurately identified AVNRT in 100% and AVRT in 95%. Induction of retro RBBB during VEST is common during EP studies for SVT. The relative change in the VH and VA intervals during retro RBBB accurately differentiates retrograde AVN from retrograde AP conduction with strong predictive accuracy. The use of retro RBBB based intervals is a useful technique facilitating the diagnosis of SVT in the EP laboratory, even in the absence of inducible tachycardia.

Background: Limited studies have described long-term outcomes in pathology confirmed multiple sclerosis (MS). Objectives: To describe long-term clinical–radiographic–cognitive outcomes in a prospectively followed cohort of patients with pathologically confirmed CNS demyelinating disease, consistent with MS. Methods: Subjects underwent clinical assessment, standardized 3T-MRI brain, and cognitive battery. Results: Seventy-five patients were included. Biopsied lesion size was ⩾ 2 cm in 62/75. At follow-up, median duration since biopsy was 11 years. Median EDSS was 3 and lesion burden was large (median 10 cm 3 ). At follow-up, 57/75 met MS criteria, 17/75 had clinically isolated syndrome, and 1 radiographic changes only. Disability scores were comparable to a prevalence cohort in Olmsted County ( p < 0.001, n = 218). Cognitive outcomes below age-normed standards included psychomotor, attention, working memory, and executive function domains. Total lesion volume and index lesion-related severity correlated with EDSS and cognitive performance. Volumetric cortical/subcortical GM correlated less than lesion metrics to cognitive outcomes. Conclusion: Despite early aggressive course in pathologically confirmed MS, its long-term course was comparable to typical MS in our study. Cognitive impairment in this group seemed to correlate strongest to index lesion severity and total lesion volume. It remains to be established how the aggressive nature of the lesion, biopsy, and treatment affect clinical/cognitive outcomes.

Abstract Glioblastoma multiforme (GBM) is a particularly aggressive primary brain tumor that is relatively common in adults. The disease comes with a dismal prognosis, often with expected survival just over a year when treated with surgery, chemotherapy, and radiation. A promising addition to our GBM treatment arsenal are oncolytic viruses (OVs), a class of immunotherapy now in clinical trials. The most effective OVs home in on tumor cells, killing them and releasing tumor-associated antigens that elicit antitumor immunity. This effectiveness, however, varies depending on the cell state—a property that may be influenced by the composition of the extracellular matrix (ECM) of GBM. Cellular communication network factor 1 (CCN1) is found in the ECM of the majority of GBMs and is predictive of resistance to OVs, particularly those derived from herpes simplex virus type 1 (HSV-1). In this study, our aim is to understand how extracellular CCN1 alters the GBM intracellular state in a manner that confers resistance to OVs. We began by using our NetDecoder platform to build CCN1-specific prioritized protein-protein interaction (PPI) networks from published LN229 human GBM transcriptomic datasets. From this network, we identified 12 PPI edges that dominate the network flow in CCN1-high LN229 cells when compared to CCN1-low controls. The 21 unique nodes that comprise these binary PPI edges were extracted and subjected to downstream biological process overrepresentation analyses using Gene Ontology. We found that the cytokine-mediated signaling pathway (FDR = 4.2 x 10-11; enrichment ratio = 15.8) and the cellular response to cytokine stimulus (FDR = 3.1 x 10-9; enrichment ratio = 10.9) were highly enriched when mapped to these nodes. We conclude that CCN1, acting as a paracrine signal in the GBM tumor microenvironment, primes the cell to inhibit HSV-1 and other candidate OV replication prior to any virus interactions, thus contributing to immunovirotherapy resistance. While CCN1 and its cell surface integrin binding partners are ostensible drug targets for overcoming this resistance, pharmacologic interventions that target CCN1-specific high flow edges in our prioritized PPI network may be more effective. Citation Format: Dileep D. Monie, Cristina Correia, Cheng Zhang, Choong Ung, Richard G. Vile, Hu Li. Innate immunity and cytokine signaling pathways drive resistance to HSV-1 oncolytic immunovirotherapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1679.

Overexpression of 11b‐hydroxysteroid dehydrogenase type 1 (11b‐HSD1) in adipose tissue leads to obesity in mice. We hypothesized that endogenous 11b‐HSD1 played a significant functional role in adipogenesis. Stable transfection of 3T3‐L1 cells with small hairpin RNA (shRNA), compared to a nucleotide‐substituted control, silenced 11b‐HSD1 expression and substantially attenuated the accumulation of lipid droplets and the expression of adipogenesis marker genes induced by a mixture containing either corticosterone or dexamethasone. 11b‐HSD1 silencing significantly elevated the concentration of 11‐dehydrocorticosterone in the culture supernatant, but did not affect the levels of corticosterone or dexamethasone, measured by LC‐MS/MS. 11b‐HSD1 silencing significantly attenuated the translocation of glucocorticoid receptors to the nucleus and reduced the number of cells entering the S phase in response to glucocorticoids (13 ± 1% vs. 30 ± 1% in control, n=5, P<0.05), a critical event in the initiation of adipogenesis. 11b‐HSD1 shRNA delivered by lentiviral vectors after the induction of differentiation reduced 11b‐HSD1 expression, but did not affect the further progression of adipogenesis. Our results established a functional and stage‐dependent role of 11b‐HSD1 in the initiation of 3T3‐L1 adipogenesis, and provided new insights into the development of obesity and related diseases.

Mutations in the γ2-subunit of AMPK (encoded by PRKAG2 gene) cause glycogen storage cardiomyopathy. We generated a mouse model with cardiac specific deletion of γ2-AMPK (cKO) to define its function in the heart. The cKO mice were born normal and remained indistinguishable from control mice under baseline conditions but developed greater cardiac hypertrophy and dysfunction after transverse aortic constriction (TAC). The total AMPK activity was normal in cKO hearts and it increased after TAC to the same extent as that of the controls. However, the γ2-AMPK activity was abolished in the cKO and the overall AMPK activity was maintained by a compensatory increase in the γ1-AMPK activity. The lack of γ2-AMPK selectively reduced hexokinase II in the cytosol resulting in decreases in glycogen content and NADPH levels. Knock-down of γ2-AMPK subunit in neonatal rat ventricle cardiomyocytes resulted in increased oxidative stress and exacerbated response to phenylephrine and H 2 O 2 , both were rescued by HKII overexpression. Taken together, these data identify isoform-specific functions of γ2-AMPK in regulating glucose and glycogen metabolism that are critical for cardiac response to stress. The results also indicate that the specific activation of γ2-AMPK is responsible for the glycogen storage cardiomyopathy associated with PRKAG2 mutations.

AbstractBackgroundOptimal timing of cardiovascular implantable electronic device (CIED) re‐implantation following device removal due to infection is undefined. Multinational guidelines reflect this and include no specific recommendation for this timing, while others have recommended waiting at least 14 days in cases of CIED related infective endocarditis (CIED‐IE). The current work seeks to clarify this issue.MethodsWe retrospectively reviewed institutional data at Mayo Clinic, Minnesota of patients aged ≥ 18 years who developed CIED‐IE from January 1, 1991 to February 1, 2016. CIED‐IE was defined as echocardiogram reported device lead or valvular vegetation. Regression analyses were used to relate the risk of clinical outcomes to the interval between CIED removal and re‐implantation and the location of vegetations.ResultsA total of 109 patients met study inclusion criteria. A majority (68.8%) of patients were men and the median age was 68.0 years. Transoesophageal echocardiogram (TEE) was performed in 95.4% of patients, with valve vegetations detected in 33.9% (n = 37). Survival analysis comparing patients in whom device re‐implantation was < 14 days vs. ≥14 days, and further categorized by those with and without valve vegetation, showed a significant difference (P = 0.028); patients with valve vegetation and reimplantation interval < 14 days had the lowest (58.7%) 12‐month survival. When adjusted for valve vegetation, longer time interval for reimplantation trended toward increased hospital length of stay (P = 0.079).ConclusionOur findings suggest that the recommended 14‐day delay between CIED extraction and re‐implantation in CIED‐IE patients is associated with a survival benefit, but longer length of hospital stay following re‐implantation.

AbstractBackgroundWe assessed the long‐term clinical outcomes of an intermediate lesion (IL) according to the presence of a combined culprit lesion (CCL).HypothesisLong‐term clinical outcomes of IL may be affected by the presence of a CCL.MethodsAngiographic findings (n = 1096) and medical chart were reviewed. Patients with IL were divided into two groups: IL without CCL group (n = 383, 64.5%) and IL with CCL group (n = 211, 35.5%).ResultsThe major adverse cardiovascular events (MACE) in the IL with CCL group were significantly higher than those in the IL without CCL group (death: 12.3% vs. 7.0%, myocardial infarction: 3.3%vs. 0.5%, stroke: 6.6% vs. 2.6%, and revascularization [RVSC]: 25.1% vs. 7.6%) during a mean follow up period of 118.4 ± 5.5 months. IL related RVSC rate in the IL with CCL group was higher than that in the IL without CCL group (5.7% vs. 2.1%, p = 0.020). RVSC rate related to IL in total subjects was lower than that related to stented lesion (3.4% vs. 6.4%). The important predictors of total MACE in total subjects were the presence of CCL, IL percent diameter stenosis, hypertension, history of percutaneous coronary intervention, blood glucose and ejection fraction. The predictors of IL related RVSC were IL percent diameter stenosis and IL located in the right coronary artery.Conclusion10‐year clinical outcomes of an IL (especially IL without CCL) were better than those of stented lesions. This study suggests that the IL can be safely followed up in sites that do not have ability to assess functional study.

Introduction: There are many treatment options for patients who have osteonecrosis of the femoral head (ONFH) and management strategies vary widely both among and within individual countries. Although many researchers have attempted to elucidate the optimal strategies for managing this disease, the lack of large-scale randomized control trials and the lack of agreement on disease staging have curtailed the development of clear-cut guidelines. Materials and Methods: The Association Research Circulation Osseous (ARCO) group sought to address three questions for the management of patients who have ONFH: 1) What imaging studies are most sensitive and specific for the diagnostic evaluation of patients who have ONFH?; 2) What is the best treatment strategy for preventing disease progression in patients who have pre-collapse lesions?; and 3) What is the best treatment strategy for patients who have post-collapse disease? The Patient, Intervention, Comparison, and Outcome (PICO) format was used to formulate the search strategy for each research question. A systematic review will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ARCO participants have been allocated to three groups, each representing one of the PICO questions. After qualitative and quantitative analysis of the data extracted from studies pertaining to each of the three research questions, a set of evidence-based clinical practice guidelines will be proposed for the management of patients who have ONFH. Discussion: It is not always clear which treatment method is optimal for the management of ONFH. Thus, many surgeons have developed and performed various procedures based on patient-specific factors. As there is no consensus on the optimal treatment for various stages of disease, it was clear that developing evidence-based clinical practice guidelines would provide more structure and uniformity to management of these patients. Therefore, the results of this systematic review will lead to the development guidelines that may improve patient-care strategies and result in better outcomes for patients who have ONFH.

Background Flow diverters (FDs) are an effective treatment for intracranial aneurysms, though not free from hemorrhagic complications. A previous study demonstrated increased vascular contractility after FD-implantation as a potential mechanism of distal complications. Our study aimed to investigate whether L-arginine medication affects vascular contractility following FD deployment in a rabbit model. Methods FDs were implanted in the aorta of normal rabbits (+FD, n = 10), with sham-operated aorta as controls (n = 5). L-Arginine was given in the drinking water (2.25% L-arginine hydrochloride) of half of the +FD animals (+FD/+Arg). Force contraction vascular contractility studies were performed on the aortic rings proximal and distal to the FD using an organ bath. Total eNOS, eNOS(pS1177), eNOS(pT495), COX-2, and S100A4 were quantified by western analysis on total protein lysates from aortic segments, normalizing to GAPDH. Results Mean vascular contractility was 53% higher in distal relative to proximal aortic segments (P = 0.0038) in +FD animals, but were not significantly different in +FD/+Arg animals, or in sham-operated controls. The +FD animals expressed significantly reduced levels of eNOS(pS1177) than sham-operated controls (P = 0.0335), while both the +FD and +FD/+Arg groups had reduced levels of eNOS(pT495) relative to sham-operated controls (P = 0.0331 and P = 0.0311, respectively). Conclusion These results suggest that L-arginine medication reduces distal vascular contractility after FD treatment via nitric oxide production and thus might mitigate risk for downstream complications.