Catheter Ablation for Hospitalized Atrial Fibrillation Patients with Reduced Systolic Function: Analysis of Inpatient Mortality, Resource Utilization and Complications.

BACKGROUND: Randomized trials have shown improvement in hard clinical end points when catheter ablation (CA) is employed as a management strategy for certain atrial fibrillation (AF) patients with heart failure and reduced ejection fraction (HFrEF). Limited data, however, exist in this realm outside the controlled clinical trial settings. We sought to determine real-world data on mortality and complications after utilization of CA in such patients. METHODS AND RESULTS: Data were derived from National Inpatient Sample from January 2008 to August 2015. Patients were identified using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. Baseline characteristics and outcomes were compared among HFrEF and AF patients undergoing CA or not. Propensity matching was done to mitigate selection bias and balance confounding variables. Various CA related complications were assessed. Logistic regression was done to determine predictors of mortality in our study cohort. A total of 2,569,919 patients were analyzed and a total of 7773 patients underwent CA. Mortality was significantly better in CA group in both unmatched (1.2% vs. 4.9%, p < 0.01) and propensity matched cohorts (1.2% vs. 3.6%, p < 0.01). Overall complication rate was 10.2% in CA cohort and primarily driven by cardiac and neurological etiologies. In regression analysis, CA remained a strong predictor of reduced mortality (OR 0.301, 95% CI 0.184-0.494). CONCLUSIONS: CA is associated with improved mortality in admitted AF patients with concomitant HFrEF. Overall complication rate after CA was modest at 10.2%. Consideration can be given to the utilization of this therapeutic modality in hospitalized AF patients with concomitant HFrEF.

Trends, Predictors and Outcomes After Utilization of Targeted Temperature Management in Cardiac Arrest Patients With Anoxic Brain Injury.

BACKGROUND: Targeted Temperature Management (TTM) is a class I recommendation for the management of sudden cardiac arrest (SCA) patients with presumed brain injury. We aimed to study trends, predictors and outcomes in SCA patients from a nationally represented US population sample. METHODS: We utilized the National Inpatient Sample from years 2005 to 2014 for the purpose of our study. Patients with SCA and anoxic brain injury were selected using relevant ICD-9 codes. Data were analyzed for trends over the years and key outcomes were assessed. Logistic regression analysis was done to determine predictors of TTM utilization in our study population. RESULTS: A total of 78,465 patients with SCA and anoxic brain injury were identified from January 2005 to December 2014. Out of these, approximately 4,481 (5.7%) patients underwent TTM. Patients that underwent TTM were younger compared to patients without TTM utilization (60.67 vs. 63.27 years, P < 0.01). African Americans, Hispanics and women were less likely to undergo TTM. Myocardial infarction, electrolyte disorders and cardiogenic shock were associated with higher odds of TTM utilization. Sepsis, renal failure and diabetes were associated with underutilization of TTM. Inpatient mortality was higher in patients who did not undergo TTM when compared to patients who underwent TTM (67.30% vs. 65.10%, P < 0.01). CONCLUSIONS: Although TTM utilization increased over our study period, the overall application of TTM was still dismal. Factors that circumvent TTM utilization need to be addressed in future studies so more eligible patients could benefit from this life saving therapy.

Atrial Fibrillation is a Risk Factor for Worse Outcomes in Patients with End Stage Liver Disease.

BACKGROUND: Liver disease is a risk factor for development of atrial fibrillation (AF). We aim to study inpatient mortality and resource utilization of end-stage liver disease (ESLD) patients with AF from a nationally representative United States population sample. METHODS: For the purpose of our study, we utilized data from National Inpatient Sample for calendar years 2005-2015. Patients with ESLD and AF were identified using relevant International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Key outcomes of inpatient mortality and resource utilization were assessed. We also constructed a multiple logistic regression model to determine predictors of mortality in ESLD patients. Propensity matching was also done to balance confounding variables. RESULTS: A total of 309,959 ESLD patients were included in final analysis. Out of these, about 32,858 (10.6%) patients have concomitant AF. ESLD patients with AF were older and had higher burden of key co-morbidities such as heart failure, diabetes and hypertension. Mortality was significantly higher in both unmatched (12.3% vs. 9.2%, p < 0.01) and matched cohorts (12.2% vs. 10.8%, p < 0.01). Additionally, ESLD patients with AF have longer length of stay, increased facility discharge and cost of hospitalization compared to ESLD patients with out AF. In multivariate analysis, AF is an independent predictor of mortality in ESLD patients. CONCLUSIONS: AF portends worse outcomes in patients with ESLD. Strong index of suspicion is warranted to timely identify AF in this patient population.

Aorto-cardiac fistula etiology, presentation, and management: A systematic review.

BACKGROUND: Aorto-cardiac fistulae are a rare but increasingly reported entity, and data are scarce. METHOD: The authors performed a systematic review of ACFs to characterize the underlying etiology, clinical presentation, and compare outcomes of treatment strategies. RESULTS: 3,733 publications were identified in the search. Of those, 292 studies including 300 patients were included. Etiology of ACFs was 38% iatrogenic, 25% infectious, 14% traumatic, and 15% due to other causes. Most patients (74%) presented with heart failure. Common locations were aortic-right atrium (37%), and aortic-pulmonary artery (25%). The majority of patients (71%) were treated surgically, while 13% were treated percutaneously, and 16% were treated conservatively. Patients who were managed conservatively had a higher mortality than those treated with invasive closure (53% vs. 12% vs. 3%, p = <0.00001). CONCLUSIONS: This systematic review sheds light on this highly morbid condition. Once recognized, fistula closure appears to be superior to conservative management.

The Feasibility and Safety of Same-Day Discharge for All Comers after Elective Percutaneous Coronary Interventions.

BACKGROUND: The safety of same day discharge (SDD) after percutaneous coronary interventions (PCI) has been demonstrated in several studies. However, SDD was only allowed in patients meeting strict criteria. We aimed to evaluate the feasibility and safety of SDD following elective-PCI in all comers. METHODS: In 2012, we implemented a strategy of SDD for all elective PCI (no exclusion) but admissions were allowed at the discretion of the treating physician. We assessed the feasibility and safety of this approach in consecutive patients who underwent elective PCI at WVU. RESULTS: Out of 3355 patients who underwent PCI between 2012 and 2016, 691 (21%) presented electively. Radial access was utilized in 480 (69.5%). Same day discharge was achieved in 539/691 (78%), and there was no difference between patients who had SDD and those who were admitted with regards to the 30-day major adverse cardiovascular and cerebrovascular events (3.2% vs. 3.5% respectively, P = 0.195). Predictors of SDD failure were procedural complications (OR 12.08, 95%CI 2.20-57.8. P = 0.002), use of Glycoprotein IIB-IIIA inhibitors (OR 3.45, 95%CI 1.067-11.41, P = 0.039), femoral access (OR 2.067, 95%CI 1.25-3.419, p = 0.005), anemia (OR 1.80, 95%CI 1.06-3.04, P = 0.029), home distance ≥60 miles (OR 1.68, 95%CI 1.03-2.72, P = 0.037). CONCLUSION: SDD is feasible in the majority of all-comers after elective PCI, and is not associated with increase in adverse events at 30-days. Certain procedural and patient's characteristics predict SDD failure. If validated in prospective studies, these factors can possibly be integrated in a predictive tool to aid in triaging patients, post-elective PCI.

Trial Sequential Analysis Comparing Bleeding and Major Adverse Cardiovascular Events in Patients with Atrial Fibrillation and Acute Coronary Syndrome on Dual versus Triple Therapy.

Objective To assess efficacy and safety of dual therapy (DT) and triple therapy (TT) in patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) with or without percutaneous coronary intervention (PCI) and evaluate the quality of evidence with respect to said outcomes based on contemporary randomized trials (RCTs). The efficacy outcome taken was major adverse cardiovascular events (MACE) while safety outcome was major bleeding events. Introduction Appropriate anti-thrombotic therapy is still controversial in patients with AF and concomitant ACS or PCI. We conducted a conventional meta-analysis pooling data from major RCTs to assess the efficacy and safety of DT and TT. Additionally, we utilized advanced analytic properties of trial sequential analysis (TSA) to assess for quality of evidence in this realm. Methods and results A total of 8,732 patients from five major RCTs were enrolled in this study. There was a statistically significant reduction in major bleeding on the DT group compared to the TT group (RR 0.65, 95% CI 0.48, 0.86). The incidence of major adverse cardiovascular events (MACE) was similar in both groups (RR 0.97, 95% CI 0.8,1.17). The trial sequential analysis showed strong evidence supporting reduction in bleeding from current major RCTs while being inconclusive based on MACE outcome. Conclusion Sufficient quality evidence could be ascertained from contemporary RCTs on reduced incidence of bleeding in DT patients compared to TT patients. Further adequately powered RCTs are needed to ensure non-inferiority of DT over TT with respect to MACE outcome.

Story of an Unfortunate Fall: Cardiac Contusion Presenting with an Atrioventricular Block.

Blunt cardiac injury (BCI), also referred to in the literature as a cardiac contusion, is a known cause of myocardial injury. It is often challenging to diagnose this condition in the absence of clear diagnostic criteria. Furthermore, its clinical presentation is highly variable depending on the severity, type, and duration of the trauma, as well as the timing from the initial insult. The clinical manifestation of BCI ranges from none to fatal arrhythmias to cardiac wall rupture seen on post-mortem examination. Cardiac biomarkers and electrocardiograms (EKG) are usually helpful in identifying cardiac trauma but are not necessarily abnormal in all cases. Falls by slipping on ice are common in the winter, but rarely do people present with a myocardial injury with these mechanical events. We describe the case of a cardiac contusion with an unusual presentation and an unusual cause, whereby both the initial EKG and troponin level were normal, and the patient presented with an atrioventricular (AV) block two weeks after "slipping on ice".

Third-degree atrioventricular block followed by syncope, labile hypertension, and orthostatic hypotension in a patient with nasopharyngeal cancer: baroreflex failure.

Baroreflex failure is a rare cause of syncope and labile blood pressures. Here, we present a case of baroreflex failure in a patient with history of nasopharyngeal cancer, status-post neck radiation. A 76-year-old male presented from an outside facility for possible pacemaker placement as he was found to have symptomatic third-degree atrioventricular (AV) block. The AV block resolved following discontinuation of the patient's his verapamil. The patient then developed labile blood pressures. A work-up for secondary causes of hypertension was negative, but due to the patient's neck radiation history, it was suggested that the labile blood pressures were due to baroreflex failure. We then started the patient on clonidine and other nonpharmacological interventions. The blood pressure was maintained after these treatments and on follow-up, the labile blood pressures had resolved. Our case demonstrates that baroreflex failure can be managed without any invasive intervention by performing frequent blood pressure measurements along with medication management.

Early-onset Lyme carditis with concurrent disseminated erythema migrans.

BACKGROUND: Lyme disease is an infection that is estimated to affect over 300,000 people in the United States annually. Typically, it presents with erythema migrans (EM), an annular rash at the site of tick attachment, within 3 to 30 days of inoculation. Untreated patients may progress to early disseminated disease. A further complication, Lyme carditis is rare but may occur several weeks later. It commonly manifests as a variable atrioventricular (AV) conduction block, with a high-grade AV block occurring in only 1% of untreated patients. This case demonstrates an unusually early presentation of Lyme carditis with complete heart block. CASE PRESENTATION: A 21-year-old male was transferred from an outside emergency department (ED) for possible pacemaker placement due to symptomatic third-degree AV block. Four days earlier the patient presented to the outside ED with fever, chills, and unrecognized EM on his right neck. He was discharged with antipyretics, but no antibiotic therapy. On the day of transfer, he returned with persistent fevers, EM now on his trunk and upper extremities, lightheadedness, and substernal chest pressure. An electrocardiogram revealed the third-degree AV block leading to transfer. Upon arrival, the patient was promptly diagnosed with Lyme carditis. Pacemaker implantation was deferred, and intravenous (IV) ceftriaxone was initiated. Within 48 hours his third-degree AV block improved to a first-degree block. By this time, his EM had also resolved. He was discharged with oral doxycycline and a 30-day event monitor, which ultimately showed persistent first-degree AV block. CONCLUSIONS: This case reinforces a unique presentation of Lyme carditis. Disseminated EM and Lyme carditis may present concurrently within 2 weeks of tick attachment. Early recognition and treatment is important for preventing progression to disseminated infection. Lyme-associated AV block will reverse within 48 to 72 hours of initiating IV antibiotic therapy and will not require pacemaker implantation. Lyme carditis should be considered in patients without heart disease who present with any degree of AV block.

The Kaposi's sarcoma-associated herpesvirus (KSHV)-induced 5-lipoxygenase-leukotriene B4 cascade plays key roles in KSHV latency, monocyte recruitment, and lipogenesis.

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). KS lesions are characterized by endothelial cells with multiple copies of the latent KSHV episomal genome, lytic replication in a low percentage of infiltrating monocytes, and inflammatory cytokines plus growth factors. We demonstrated that KSHV utilizes inflammatory cyclooxygenase 2/prostaglandin E2 to establish and maintain latency (Sharma-Walia, N., A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog 6:e1000777, 2010 [doi:10.1371/journal.ppat.1000777]). Here, we evaluated the role of 5-lipoxygenase (5LO) and its chemotactic metabolite leukotriene B4 (LTB4) in KSHV biology. Abundant staining of 5LO was detected in human KS tissue sections. We observed elevated levels of 5LO and high levels of secretion of LTB4 during primary KSHV infection of endothelial cells and in PEL B cells (BCBL-1 and BC-3 cells). Blocking the 5LO/LTB4 cascade inhibited viral latent ORF73, immunomodulatory K5, viral macrophage inflammatory protein 1 (MIP-1), and viral MIP-2 gene expression, without much effect on lytic switch ORF50, immediate early lytic K8, and viral interferon-regulatory factor 2 gene expression. 5LO inhibition significantly downregulated latent viral Cyclin and latency-associated nuclear antigen 2 levels in PEL cells. 5LO/LTB4 inhibition downregulated TH2-related cytokine secretion, elevated TH1-related cytokine secretion, and reduced human monocyte recruitment, adhesion, and transendothelial migration. 5LO/LTB4 inhibition reduced fatty acid synthase (FASN) promoter activity and its expression. Since FASN, a key enzyme required in lipogenesis, is important in KSHV latency, these findings collectively suggest that 5LO/LTB4 play important roles in KSHV biology and that effective inhibition of the 5LO/LTB4 pathway could potentially be used in treatment to control KS/PEL.

Phosphorylation and polyubiquitination of transforming growth factor beta-activated kinase 1 are necessary for activation of NF-kappaB by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor.

Kaposi's sarcoma-associated herpesvirus (KSHV) G protein-coupled receptor (vGPCR) protein has been shown to induce several signaling pathways leading to the modulation of host gene expression. The hijacking of these pathways facilitates the viral life cycle and leads to tumorigenesis. In the present work, we show that transforming growth factor ß (TGF-ß)-activated kinase 1 (TAK1) is an important player in NF-κB activation induced by vGPCR. We observed that the expression of an inactive TAK1 kinase mutant (TAK1M) reduces vGPCR-induced NF-κB nuclear translocation and transcriptional activity. Consequently, the expression of several NF-κB target genes normally induced by vGPCR was blocked by TAK1M expression, including interleukin 8 (IL-8), Gro1, IκBα, COX-2, cIAP2, and Bcl2 genes. Similar results were obtained after downregulation of TAK1 by small interfering RNA (siRNA) technology. The expression of vGPCR recruited TAK1 to the plasma membrane, and vGPCR interacts with TAK1. vGPCR expression also induced TAK1 phosphorylation and lysine 63-linked polyubiquitination, the two markers of the kinase's activation. Finally, inhibition of TAK1 by celastrol inhibited vGPCR-induced NF-κB activation, indicating this natural compound could be used as a potential therapeutic drug against KSHV malignancies involving vGPCR.

NFAT and CREB regulate Kaposi's sarcoma-associated herpesvirus-induced cyclooxygenase 2 (COX-2).

COX-2 has been implicated in Kaposi's sarcoma-associated herpesvirus (KSHV) latency and pathogenesis (A. George Paul, N. Sharma-Walia, N. Kerur, C. White, and B. Chandran, Cancer Res. 70:3697-3708, 2010; P. P. Naranatt, H. H. Krishnan, S. R. Svojanovsky, C. Bloomer, S. Mathur, and B. Chandran, Cancer Res. 64:72-84, 2004; N. Sharma-Walia, A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog. 6:e1000777, 2010; N. Sharma-Walia, H. Raghu, S. Sadagopan, R. Sivakumar, M. V. Veettil, P. P. Naranatt, M. M. Smith, and B. Chandran, J. Virol. 80:6534-6552, 2006). However, the precise regulatory mechanisms involved in COX-2 induction during KSHV infection have never been explored. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 upon KSHV de novo infection. Promoter analysis using human COX-2 promoter deletion and mutation reporter constructs revealed that nuclear factor of activated T cells (NFAT) and the cyclic AMP (cAMP) response element (CRE) modulate KSHV-mediated transcriptional regulation of COX-2. Along with multiple KSHV-induced signaling pathways, infection-induced prostaglandin E(2) (PGE(2)) also augmented COX-2 transcription. Infection of endothelial cells markedly induced COX-2 expression via a cyclosporine A-sensitive, calcineurin/NFAT-dependent pathway. KSHV infection increased intracellular cAMP levels and activated protein kinase A (PKA), which phosphorylated the CRE-binding protein (CREB) at serine 133, which probably led to interaction with CRE in the COX-2 promoter, thereby enhancing COX-2 transcription. PKA selective inhibitor H-89 pretreatment strongly inhibited CREB serine 133, indicating the involvement of a cAMP-PKA-CREB-CRE loop in COX-2 transcriptional regulation. In contrast to phosphatidylinositol 3-kinase and protein kinase C, inhibition of FAK and Src effectively reduced KSHV infection-induced COX-2 transcription and protein levels. Collectively, our study indicates that mediation of COX-2 transcription upon KSHV infection is a paradigm of a complex regulatory milieu involving the interplay of multiple signal cascades and transcription factors. Intervention at each step of COX-2/PGE(2) induction can be used as a potential therapeutic target to treat KSHV-associated neoplasm and control inflammatory sequels of KSHV infection.