Research Spotlight

Gibson, C. M., M. J. Mack, V. T. Lee, D. J. Schneider, F. W. Sellke, E. M. Ohman, V. H. Thourani, G. Doros, H. Kroger, D. E. Cutlip and E. N. Deliargyris (2021). “Rationale and Design of the Safe and Timely Antithrombotic Removal – Ticagrelor (STAR-T) Trial: A Prospective, Multi-center, Double-blind, Randomized Controlled Trial Evaluating Reductions in Postoperative Bleeding with Intraoperative Removal of Ticagrelor by the DrugSorb™-ATR Device in Patients Undergoing Cardiothoracic Surgery within 48hrs from Last Ticagrelor Dose.” Am Heart J Nov 1; S0002-8703(21)00442-7. [Epub ahead of print].

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Ticagrelor is often administered to patients with acute coronary syndromes. However, when these patients require urgent or emergent cardiothoracic (CT) surgery the presence of ticagrelor significantly increases surgical bleeding. The goal of the current trial is to evaluate the effectiveness and safety of the DrugSorb™-ATR hemoadsorption device for the intraoperative removal of ticagrelor to reduce postoperative bleeding in the above patient population. The Safe and Timely Antithrombotic Removal – Ticagrelor (STAR-T) Trial is a multi-center, double-blind, randomized, controlled trial enrolling patients who require cardiothoracic surgery on cardiopulmonary bypass (CPB) within 48 hours of last ticagrelor dose. Subjects will be randomized 1:1 to receive either the DrugSorb™-ATR device or an identical sham device during CPB. The study will enroll up to 120 subjects at 20 U.S centers, and the primary outcome is the composite of fatal perioperative bleeding, moderate/severe/massive bleeding according to the Universal Definition of Perioperative Bleeding in Cardiac Surgery (UDPB), and 24hr chest tube drainage. The components of the composite are hierarchically ranked according to clinical significance and the primary analysis will utilize the Win Ratio method. Percent change in ticagrelor levels before and after CPB (drug removal) will be the key secondary endpoint. An independent Clinical Events Committee will adjudicate all clinical endpoints including safety endpoints relating to postoperative thrombotic events. Subjects will be followed through 30 days after the index operation. The results from STAR-T, if positive, will potentially support FDA clearance of the device.

Gelijns, A. C., A. J. Moskowitz, P. T. O’Gara, G. Giustino, M. J. Mack, D. M. Mancini, E. Bagiella, J. Hung, G. Ailawadi, M. B. Leon, M. A. Acker, J. H. Alexander, N. W. Dickert, W. C. Taddei-Peters and M. A. Miller (2021). “Transcatheter mitral valve repair for functional mitral regurgitation: Evaluating the evidence.” J Thorac Cardiovasc Surg 162(5): 1504-1511.

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OBJECTIVES: Two trials (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation Trial and Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation Trial) were published in 2018 evaluating the effectiveness and safety of transcatheter repair for patients with heart failure with significant functional mitral regurgitation, which yielded different results. This article reviews the strength of the evidence, differences in trial designs, ethical and implementation implications, and delineates future research needs to help guide the appropriate dissemination of transcatheter repair for functional patients with mitral regurgitation. METHODS: The National Heart, Lung, and Blood Institute convened a workshop of interdisciplinary experts to address these objectives. RESULTS: Transcatheter repair of functional mitral regurgitation can provide significant benefits in terms of heart failure hospitalizations, survival, and quality of life when appropriate heart failure candidates with moderate to severe or severe mitral regurgitation while on optimal guideline-directed medical therapy can be identified. Key ingredients for success are preoperative evaluation and management and postoperative care by an interdisciplinary heart team. CONCLUSIONS: Given the discordance observed between trials, ongoing innovation in patient management, and potential expansion of indications for use, the evidence base must be expanded to optimize appropriate implementation of this complex therapy. This will require more complete capture of outcome data in real-world settings for all eligible candidates whether or not they receive this therapy. Inevitably, the indications for use of this therapy will expand, as will the devices and therapeutic approaches for this population, necessitating the study of comparative effectiveness through randomized trials or observational studies. Moreover, given the substantial variations in care delivery, conducting implementation research to delineate characteristics of the optimal care model would be of benefit.

Kim, W. Y., I. Kugasia, G. Pearson and O. Epelbaum (2021). “Dramatic Ventricular Shunt Complications in Pulmonary and Critical Care Medicine.” Am J Respir Crit Care Med 204(9): e94-e96.

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A 29-year-old man with bilateral ventriculoperitoneal shunts (VPS) underwent left shunt revision with replacement of the valve and distal catheter. On postoperative Day 1, he developed subcutaneous emphysema (SE) from the neck to the scrotum. Chest radiography demonstrated SE without pneumothorax (Figure 1A). Chest computed tomography (CT) (Video 1) showed widespread SE without pneumoperitoneum. The next day, sepsis and progressive SE were noted. Abdominal CT showed the VPS catheter perforating into the small intestine with its tip inside the lumen (Figure 1B). Following emergent laparotomy with resection of the perforated segment, the patient’s truncal SE resolved (Video 2). Despite a prolonged postoperative course, he was ultimately transferred from our institution in stable condition.[No abstract; excerpt from article].

Carlson, D. A., C. P. Gyawali, A. Khan, R. Yadlapati, J. Chen, R. V. Chokshi, J. O. Clarke, J. M. Garza, A. S. Jain, P. Katz, V. Konda, K. Lynch, F. H. Schnoll-Sussman, S. J. Spechler, M. F. Vela, J. E. Prescott, A. J. Baumann, E. N. Donnan, W. Kou, P. J. Kahrilas and J. E. Pandolfino (2021). “Classifying Esophageal Motility by FLIP Panometry: A Study of 722 Subjects With Manometry.” Am J Gastroenterol Oct 10. [Epub ahead of print].

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INTRODUCTION: Functional luminal imaging probe (FLIP) panometry can evaluate esophageal motility in response to sustained esophageal distension at the time of sedated endoscopy. This study aimed to describe a classification of esophageal motility using FLIP panometry and evaluate it against high-resolution manometry (HRM) and Chicago Classification v4.0 (CCv4.0). METHODS: Five hundred thirty-nine adult patients who completed FLIP and HRM with a conclusive CCv4.0 diagnosis were included in the primary analysis. Thirty-five asymptomatic volunteers (“controls”) and 148 patients with an inconclusive CCv4.0 diagnosis or systemic sclerosis were also described. Esophagogastric junction (EGJ) opening and the contractile response (CR) to distension (i.e., secondary peristalsis) were evaluated with a 16-cm FLIP during sedated endoscopy and analyzed using a customized software program. HRM was classified according to CCv4.0. RESULTS: In the primary analysis, 156 patients (29%) had normal motility on FLIP panometry, defined by normal EGJ opening and a normal or borderline CR; 95% of these patients had normal motility or ineffective esophageal motility on HRM. Two hundred two patients (37%) had obstruction with weak CR, defined as reduced EGJ opening and absent CR or impaired/disordered CR, on FLIP panometry; 92% of these patients had a disorder of EGJ outflow per CCv4.0. DISCUSSION: Classifying esophageal motility in response to sustained distension with FLIP panometry parallels the swallow-associated motility evaluation provided with HRM and CCv4.0. Thus, FLIP panometry serves as a well-tolerated method that can complement, or in some cases be an alternative to HRM, for evaluating esophageal motility disorders.

Shimura, T., R. Kandimalla, Y. Okugawa, M. Ohi, Y. Toiyama, C. He and A. Goel (2021). “Novel evidence for m(6)A methylation regulators as prognostic biomarkers and FTO as a potential therapeutic target in gastric cancer.” Br J Cancer.

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BACKGROUND: While emerging evidence indicates that N(6)-methyladenosine (m(6)A) regulators play crucial roles in cancer progression, their clinical significance in gastric cancer (GC) has thus far not been elucidated. METHODS: We investigated the expression of the m(6)A regulator genes and their prognostic potential in a large clinical cohort of 173 GC patients using qRT-PCR assays. In addition, we undertook a series of in-vitro and in-vivo functional studies to investigate the oncogenic role of FTO. RESULTS: GC patients with low expression of METTL3, METTL14, ALKBH5, WTAP and YTHDF1 demonstrated significantly poor OS, while patients with high FTO expression exhibited markedly worse OS. Furthermore, the cumulative risk-score derived from these gene panel also significantly associated with poor OS, with a corresponding hazard ratio of 5.47 (95% CI: 3.18-9.41, p < 0.0001). We observed that FTO expression was frequently upregulated in GC cell lines, with epithelial-mesenchymal-transition (EMT) features. FTO knockdown in HGC27 and AGS cells inhibited cell proliferation and migratory potential, while its overexpression in MKN28 cells resulted in enhanced proliferation and migration. Finally, confirming our in-vitro findings, FTO suppression led to significant tumour growth inhibition in a HGC27 xenograft model. CONCLUSIONS: We demonstrate that m(6)A regulators may serve as promising prognostic biomarkers in GC. Our functional studies reveal that FTO is an important oncogene and may be a promising therapeutic target associated with EMT-alterations in gastric cancer.