Clinical and Structural Factors Affecting Ablation Outcomes in Atrial Fibrillation Patients - A Review.

Catheter ablation is an effective and durable treatment option for patients with atrial fibrillation (AF). Ablation outcomes vary widely, with optimal results in patients with paroxysmal AF and diminishing results in patients with persistent or long-standing persistent AF. A number of clinical factors including obesity, hypertension, diabetes, obstructive sleep apnea, and alcohol use contribute to AF recurrence following ablation, likely through modulation of the atrial electroanatomic substrate. In this article, we review the clinical risk factors and the electro-anatomic features that contribute to AF recurrence in patients undergoing ablation for AF.

Relationship between amiodarone response prior to ablation and 1-year outcomes of catheter ablation for atrial fibrillation.

INTRODUCTION: Catheter ablation for atrial fibrillation (AF) is a common therapeutic strategy for patients with either paroxysmal AF (PAF) or persistent AF (persAF), but long-term ablation success rates are imperfect. Maintenance of sinus rhythm immediately before ablation with antiarrhythmic drug (AAD) therapy has been associated with improved outcomes in patients undergoing ablation. Amiodarone has superior efficacy relative to other AADs. Whether failure of amiodarone to maintain sinus rhythm before ablation for either PAF or persAF is associated with poor outcomes is unknown. METHODS: A total of 307 patients who received amiodarone in a 1-year window before undergoing catheter ablation for AF were included. Patients were divided into amiodarone success (n = 183) and amiodarone failure (n = 124) groups based on the response to pre-ablation amiodarone treatment. Analysis of procedural outcomes as a function of response to amiodarone therapy was performed. Patients were followed for at least 12 months postablation, to assess outcomes (adverse events and arrhythmia recurrence). Procedural success was defined by the absence of documented arrhythmia (>30 s) without any antiarrhythmic agents beyond a 90-day blanking period. RESULTS: Following ablation for either PAF or persAF, freedom from any recurrent atrial arrhythmia at 1 year was 57.7% for the entire cohort. One-year freedom from recurrent arrhythmia in the amiodarone success group was comparable to that in the amiodarone failure group (55.7% vs. 60.5%; p = .54). Success rates following ablation did not vary by the response to amiodarone when analyzed for PAF or persAF subgroups. CONCLUSION: Failure to restore and maintain sinus rhythm with amiodarone before ablation for either PAF or persAF is not a predictor of ablation procedural failure. Amiodarone failure alone should not deter practitioners from considering ablation therapy for patients with AF.

A Rare Case of MRSA Pericarditis with Expanding, Purulent Pericardial Effusion Leading to Uremic Kidney Failure from a Right, Necrotic Toe.

Purulent pericarditis is an extremely rare entity with only a few reported cases so far. This condition deserves prompt diagnosis because of its significant mortality rate if left untreated. A 76-year-old man with a past medical history of coronary artery disease (CAD) with percutaneous coronary intervention (PCI) to the left anterior descending artery (LAD) and right circumflex artery (RCA), ischemic cardiomyopathy with moderately reduced ejection fraction (EF 45-50%), peripheral artery disease (PAD), COVID-19 pneumonia complicated by fibrotic lung disease (on 3 liters of home oxygen), type-2 diabetes mellitus (T2DM), hypertension (HTN), hyperlipidemia (HLD), and chronic kidney disease (CKD) stage III presented with complaints of pleuritic chest pain and shortness of breath. On hospital day 1, he was afebrile and hemodynamically stable with physical exam remarkable for bibasilar crackles and dry gangrene of his right first toe. He developed progressive altered mental status, hypotension, oliguric renal failure, and respiratory distress on hospital day 6. On exam at this time, he had an elevated jugular venous distension (JVD) of 12-14 cm water, pericardial friction rub with decreased heart sounds, and orthopnea; all were consistent with cardiac tamponade clinically. An electrocardiogram (EKG) showed new ST elevations in leads I, II, and aVL with ST depression in aVR and V1 with only mild elevation in troponin I to 0.07 ng/mL. A transthoracic echocardiogram (TTE) was done on hospital day 7 and showed a moderate sized pericardial effusion with inferior vena cava (IVC) enlargement but no atrial collapse, ventricular collapse, IVC collapse, or respiratory variation in the mitral and tricuspid inflow velocities. Blood cultures grew methicillin-resistant Staphylococcus aureus (MRSA) on hospital day 6, and he was started on intravenous (IV) vancomycin. The differential diagnosis for his enlarging pericardial effusion included purulent pericarditis, uremic pericarditis, or hemorrhagic effusion. He had urgent diagnostic and therapeutic pericardiocentesis with removal of 350 milliliters of fluid. The pericardial fluid was cloudy, tan-brown with a gram stain showing gram-positive cocci in clusters and cultures growing MRSA, which confirmed the diagnosis of purulent pericarditis secondary to MRSA infection. After the pericardiocentesis, his blood pressure, respiratory distress, and renal failure improved. The source of the bacteremia was from osteomyelitis of his gangrenous, right toe with bone biopsy growing both MRSA and Streptococcus anginosus. He underwent toe amputation for definitive source control. He was discharged on hospital day 24 with a plan to complete 6 weeks of IV vancomycin.

Sump syndrome of the remnant common bile duct following a living donor liver transplant.

Sump syndrome - a collection of digested food, debris, stones, bile, and bacteria in a poorly drained, bile duct reservoir - occurs most commonly after a side-to-side choledochoduodenostomy. As choledochoduodenostomies are now less common, sump syndrome is more often characterized as a complication of Roux-en-Y hepaticojejunostomies; however, most cases occur at the hepaticojejunostomy anastomosis. We report a rare case of sump syndrome in the intra-pancreatic remnant common bile duct in a patient with primary sclerosing cholangitis following living donor liver transplant via Roux-en-Y hepaticojejunostomy. Our patient had a history of end-stage liver disease secondary to primary sclerosing cholangitis but presented with recurrent bacteremia and symptoms of acute cholangitis following her transplant. While this complication has not been reported in this population, we know that those with primary sclerosing cholangitis and those undergoing liver transplantation are at very high risk for biliary complications and strictures. Liver transplant is currently our only treatment for primary sclerosing cholangitis, and more than any other group, they are referred for living donor liver transplantation, preferably via Roux-en-Y hepaticojejunostomy. Thus, our patient's clinical scenario is not uncommon and demonstrates a source of serious infection of which providers must be aware.

Global Effects of DDX3 Inhibition on Cell Cycle Regulation Identified by a Combined Phosphoproteomics and Single Cell Tracking Approach.

DDX3 is an RNA helicase with oncogenic properties. The small molecule inhibitor RK-33 is designed to fit into the ATP binding cleft of DDX3 and hereby block its activity. RK-33 has shown potent activity in preclinical cancer models. However, the mechanism behind the antineoplastic activity of RK-33 remains largely unknown. In this study we used a dual phosphoproteomic and single cell tracking approach to evaluate the effect of RK-33 on cancer cells. MDA-MB-435 cells were treated for 24 hours with RK-33 or vehicle control. Changes in phosphopeptide abundance were analyzed with quantitative mass spectrometry using isobaric mass tags (Tandem Mass Tags). At the proteome level we mainly observed changes in mitochondrial translation, cell division pathways and proteins related to cell cycle progression. Analysis of the phosphoproteome indicated decreased CDK1 activity after RK-33 treatment. To further evaluate the effect of DDX3 inhibition on cell cycle progression over time, we performed timelapse microscopy of Fluorescent Ubiquitin Cell Cycle Indicators labeled cells after RK-33 or siDDX3 exposure. Single cell tracking indicated that DDX3 inhibition resulted in a global delay in cell cycle progression in interphase and mitosis. In addition, we observed an increase in endoreduplication. Overall, we conclude that DDX3 inhibition affects cells in all phases and causes a global cell cycle progression delay.

Combination treatment using DDX3 and PARP inhibitors induces synthetic lethality in BRCA1-proficient breast cancer.

Triple-negative breast cancers have unfavorable outcomes due to their inherent aggressive behavior and lack of targeted therapies. Breast cancers occurring in BRCA1 mutation carriers are mostly triple-negative and harbor homologous recombination deficiency, sensitizing them to inhibition of a second DNA damage repair pathway by, e.g., PARP inhibitors. Unfortunately, resistance against PARP inhibitors in BRCA1-deficient cancers is common and sensitivity is limited in BRCA1-proficient breast cancers. RK-33, an inhibitor of the RNA helicase DDX3, was previously demonstrated to impede non-homologous end-joining repair of DNA breaks. Consequently, we evaluated DDX3 as a therapeutic target in BRCA pro- and deficient breast cancers and assessed whether DDX3 inhibition could sensitize cells to PARP inhibition. High DDX3 expression was identified by immunohistochemistry in breast cancer samples of 24% of BRCA1 (p = 0.337) and 21% of BRCA2 mutation carriers (p = 0.624), as compared to 30% of sporadic breast cancer samples. The sensitivity to the DDX3 inhibitor RK-33 was similar in BRCA1 pro- and deficient breast cancer cell lines, with IC50 values in the low micromolar range (2.8-6.6 µM). A synergistic interaction was observed for combination treatment with RK-33 and the PARP inhibitor olaparib in BRCA1-proficient breast cancer, with the mean combination index ranging from 0.59 to 0.62. Overall, we conclude that BRCA pro- and deficient breast cancers have a similar dependency upon DDX3. DDX3 inhibition by RK-33 synergizes with PARP inhibitor treatment, especially in breast cancers with a BRCA1-proficient background.

Identification of the DEAD box RNA helicase DDX3 as a therapeutic target in colorectal cancer.

Identifying druggable targets in the Wnt-signaling pathway can optimize colorectal cancer treatment. Recent studies have identified a member of the RNA helicase family DDX3 (DDX3X) as a multilevel activator of Wnt signaling in cells without activating mutations in the Wnt-signaling pathway. In this study, we evaluated whether DDX3 plays a role in the constitutively active Wnt pathway that drives colorectal cancer. We determined DDX3 expression levels in 303 colorectal cancers by immunohistochemistry. 39% of tumors overexpressed DDX3. High cytoplasmic DDX3 expression correlated with nuclear ß-catenin expression, a marker of activated Wnt signaling. Functionally, we validated this finding in vitro and found that inhibition of DDX3 with siRNA resulted in reduced TCF4-reporter activity and lowered the mRNA expression levels of downstream TCF4-regulated genes. In addition, DDX3 knockdown in colorectal cancer cell lines reduced proliferation and caused a G1 arrest, supporting a potential oncogenic role of DDX3 in colorectal cancer. RK-33 is a small molecule inhibitor designed to bind to the ATP-binding site of DDX3. Treatment of colorectal cancer cell lines and patient-derived 3D cultures with RK-33 inhibited growth and promoted cell death with IC50 values ranging from 2.5 to 8 µM. The highest RK-33 sensitivity was observed in tumors with wild-type APC-status and a mutation in CTNNB1. Based on these results, we conclude that DDX3 has an oncogenic role in colorectal cancer. Inhibition of DDX3 with the small molecule inhibitor RK-33 causes inhibition of Wnt signaling and may therefore be a promising future treatment strategy for a subset of colorectal cancers.