Research Spotlight

Que, J., K. S. Garman, R. F. Souza and S. J. Spechler (2019). “Pathogenesis and Cells of Origin of Barrett’s Esophagus.” Gastroenterology May 10. [Epub ahead of print].

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In patients with Barrett’s esophagus (BE), metaplastic columnar mucosa, containing epithelial cells with gastric and intestinal features, replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease. This condition is estimated to affect 5.6% of adults in the United States, and is a major risk factor for esophageal adenocarcinoma. Despite the prevalence and importance of BE, its pathogenesis is incompletely understood and there are disagreements over the cells of origin. We review mechanisms of BE pathogenesis, including transdifferentiation and transcommitment, and discuss potential cells of origin including basal cells of the squamous epithelium, cells of esophageal submucosal glands and their ducts, cells of the proximal stomach, and specialized populations of cells at the esophago-gastric junction (residual embryonic cells and transitional basal cells). We discuss the concept of metaplasia as a wound-healing response, and how cardiac mucosa might be the precursor of the intestinal metaplasia of BE. Finally, we discuss shortcomings in current diagnostic criteria for BE that have important clinical implications.

Kandimalla, R., T. Ozawa, F. Gao, X. Wang and A. Goel (2019). “Gene Expression Signature in Surgical Tissues and Endoscopic Biopsies Identifies High-Risk T1 Colorectal Cancers.” Gastroenterology 156(8): 2338-2341.e2333.

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We for the first time identify and validate a novel, mRNA-based signature for the identification of LNM in patients with submucosal T1 CRC. Although we are enthused by the performance of our biomarkers even in presurgical biopsies, we would like to acknowledge that the overall performance of our assay in these biopsy tissues was somewhat lower than resected specimens (AUC of 0.72 vs 0.88). Furthermore, it is encouraging to notice that the robustness of our current mRNA assay was quite comparable to the miRNA biomarkers that we reported previously. Currently we are planning prospective studies to evaluate the performance of both mRNA and miRNA panels, individually, as well as in combination, to determine whether a combined classifier may offer superior accuracy in identifying LNM in T1 CRCs, especially in presurgical biopsies. If successful, presurgical use of this signature might lead to reduction in endoscopic submucosal dissection-associated complications (perforation or bleeding), as well as in reducing the overall health care economic burden from such expensive surgical procedures. Ours was a retrospective study; hence, future prospective studies must independently validate the robustness of these biomarkers before their translation into clinical practice. (Excerpt from text, p. 2340; no abstract available.)

Balmforth, C., J. Simpson, L. Shen, P. S. Jhund, M. Lefkowitz, A. R. Rizkala, J. L. Rouleau, V. Shi, S. D. Solomon, K. Swedberg, M. R. Zile, M. Packer and J. J. V. McMurray (2019). “Outcomes and Effect of Treatment According to Etiology in HFrEF: An Analysis of PARADIGM-HF.” JACC Heart Fail 7(6): 457-465.

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OBJECTIVES: The purpose of this study was to compare outcomes (and the effect of sacubitril/valsartan) according to etiology in the PARADIGM-HF (Prospective comparison of angiotensin-receptor-neprilysin inhibitor [ARNI] with angiotensin-converting-enzyme inhibitor [ACEI] to Determine Impact on Global Mortality and morbidity in Heart Failure) trial. BACKGROUND: Etiology of heart failure (HF) has changed over time in more developed countries and is also evolving in non-Western societies. Outcomes may vary according to etiology, as may the effects of therapy. METHODS: We examined outcomes and the effect of sacubtril/valsartan according to investigator-reported etiology in PARADIGM-HF. The outcomes analyzed were the primary composite of cardiovascular death or HF hospitalization, and components, and death from any cause. Outcomes were adjusted for known prognostic variables including N terminal pro-B type natriuretic peptide. RESULTS: Among the 8,399 patients randomized, 5,036 patients (60.0%) had an ischemic etiology. Among the 3,363 patients (40.0%) with a nonischemic etiology, 1,595 (19.0% of all patients; 47% of nonischemic patients) had idiopathic dilated cardiomyopathy, 968 (11.5% of all patients; 28.8% of nonischemic patients) had a hypertensive cause, and 800 (9.5% of all patients, 23.8% of nonischemic patients) another cause (185 infective/viral, 158 alcoholic, 110 valvular, 66 diabetes, 30 drug-related, 14 peripartum-related, and 237 other). Whereas the unadjusted rates of all outcomes were highest in patients with an ischemic etiology, the adjusted hazard ratios (HRs) were not different from patients in the 2 major nonischemic etiology categories; for example, for the primary outcome, compared with ischemic (HR: 1.00), hypertensive 0.87 (95% confidence interval [CI]: 0.75 to 1.02), idiopathic 0.92 (95% CI: 0.82 to 1.04) and other 1.00 (95% CI: 0.85 to 1.17). The benefit of sacubitril/valsartan over enalapril was consistent across etiologic categories (interaction for primary outcome; p = 0.11). CONCLUSIONS: Just under one-half of patients in this global trial had nonischemic HF with reduced ejection fraction, with idiopathic and hypertensive the most commonly ascribed etiologies. Adjusted outcomes were similar across etiologic categories, as was the benefit of sacubitril/valsartan over enalapril. (Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure; NCT01035255).

Bax, J. J., V. Delgado, R. T. Hahn, J. Leipsic, J. K. Min, P. Grayburn, L. Sondergaard, S. H. Yoon and S. Windecker (2019). “Transcatheter Aortic Valve Replacement: Role of Multimodality Imaging in Common and Complex Clinical Scenarios.” JACC Cardiovasc Imaging May 9. [Epub ahead of print].

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Transcatheter aortic valve replacement (TAVR) is an established therapy for patients with symptomatic severe aortic stenosis. Technological advances and the learning curve have resulted in better procedural results in terms of hemodynamic valve performance and intermediate-term clinical outcomes. The integration of anatomical and functional information provided by multimodality imaging has improved size selection of TAVR prostheses, permitted better patient selection, and provided new insights in the performance of the TAVR prostheses at follow-up. Furthermore, the field of TAVR continues to develop and expand the technique to younger patients with lower risk on the one hand, and more complex clinical scenarios, on the other hand, such as degenerated aortic bioprostheses, bicuspid aortic valves, or pure native aortic regurgitation. The present review article summarizes how multimodality imaging can be integrated in TAVR in clinical (sometimes complex) scenarios that have not been included in the landmark randomized clinical trials.

Giustino, G., J. Overbey, D. Taylor, G. Ailawadi, K. Kirkwood, J. DeRose, M. A. Gillinov, F. Dagenais, M. L. Mayer, A. Moskowitz, E. Bagiella, M. Miller, P. Grayburn, P. K. Smith, A. Gelijns, P. O’Gara, M. Acker, A. Lala and J. Hung (2019). “Sex-Based Differences in Outcomes After Mitral Valve Surgery for Severe Ischemic Mitral Regurgitation: From the Cardiothoracic Surgical Trials Network.” JACC Heart Fail 7(6): 481-490.

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OBJECTIVES: This study investigated sex-based differences in outcomes after mitral valve (MV) surgery for severe ischemic mitral regurgitation (SIMR). BACKGROUND: Whether differences in outcomes exist between men and women after surgery for SIMR remains unknown. METHODS: Patients enrolled in a randomized trial comparing MV replacement versus MV repair for SIMR were included and followed for 2 years. Endpoints for this analysis included all-cause mortality, major adverse cardiovascular and cerebrovascular events (MACCE) (defined as the composite of death, stroke, hospitalization for heart failure, worsening New York Heart Association functional class or MV re-operation), quality of life (QOL), functional status, and percentage of change in left ventricular end-systolic volume index (LVESVI) from baseline through 2 years. RESULTS: Of 251 patients enrolled in the trial, 96 (38.2%) were women. Compared with men, women had smaller LV volumes and effective regurgitant orifice areas (EROA) but greater EROA/left ventricular (LV) end-diastolic volume ratios. At 2 years, women had higher rates of all-cause mortality (27.1% vs. 17.4%, respectively; adjusted hazard ratio [adjHR]: 1.85; 95% confidence interval [CI]: 1.05 to 3.26; p = 0.03) and of MACCE (49.0% vs. 38.1%, respectively; adjHR: 1.58; 95% CI: 1.06 to 2.37; p = 0.02). Women also reported worse QOL and functional status at 2 years. There were no significant differences in the percentage of change over 2 years in LVESVI between women and men (adjbeta: -10.4; 95% CI: -23.4 to 2.6; p = 0.12). CONCLUSIONS: Women with SIMR displayed different echocardiographic features and experienced higher mortality and worse QOL after MV surgery than men. There were no significant differences in the degree of reverse LV remodeling between sexes. (Comparing the Effectiveness of Repairing Versus Replacing the Heart’s Mitral Valve in People With Severe Chronic Ischemic Mitral Regurgitation [Severe Ischemic Mitral Regurgitation]; NCT00807040).