Research Spotlight

Bohm, M., R. Young, P. S. Jhund, S. D. Solomon, J. Gong, M. P. Lefkowitz, A. R. Rizkala, J. L. Rouleau, V. C. Shi, K. Swedberg, M. R. Zile, M. Packer and J. J. V. McMurray (2017). “Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (lcz696) in patients with chronic heart failure and reduced ejection fraction: Results from paradigm-hf.” Eur Heart J 38(15): 1132-1143.

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Background: Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP. Methods: We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and >/=140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP. Findings: All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74-1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65-1.02) for those with a SBP >/=140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP. Interpretation: In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP.

Cortazar, F. B., W. F. Pendergraft, 3rd, J. Wenger, C. T. Owens, K. Laliberte and J. L. Niles (2017). “Effect of continuous b cell depletion with rituximab on pathogenic autoantibodies and total igg levels in antineutrophil cytoplasmic antibody-associated vasculitis.” Arthritis Rheumatol 69(5): 1045-1053.

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OBJECTIVE: To evaluate the effect of rituximab on pathogenic autoantibodies and total Ig levels, and to identify serious adverse events in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with continuous B cell depletion. METHODS: We conducted a retrospective analysis of 239 patients with AAV treated with rituximab-induced continuous B cell depletion. Two treatment cohorts were analyzed: an induction group (n = 52) and a maintenance group (n = 237). Changes in ANCA titers and total Ig levels over time were evaluated using mixed-effects models. Risk factors for serious infections during maintenance treatment were evaluated using Poisson regression. RESULTS: During induction, IgG levels fell at a mean rate of 6% per month (95% confidence interval [95% CI] 4, 8%), while ANCA levels declined at a mean rate of 47% per month (95% CI 42, 52%) and 48% per month (95% CI 42, 54%) for patients with antimyeloperoxidase (anti-MPO) antibodies and those with anti-proteinase 3 (anti-PR3) antibodies, respectively. During maintenance treatment, with a median duration of 2.4 years (interquartile range 1.5, 4.0 years), IgG levels declined a mean of 0.6% per year (95% CI -0.2, 1.4%). New significant hypogammaglobulinemia (IgG level of <400 mg/dl) during maintenance treatment occurred in 4.6% of the patients, all of whom were in the lowest baseline IgG quartile. Serious infections during maintenance therapy occurred at a rate of 0.85 per 10 patient-years (95% CI 0.66, 1.1) and were independently associated with an IgG level of <400 mg/dl. CONCLUSION: B cell-targeted therapy causes a preferential decline in ANCA titers relative to total IgG levels. Despite prolonged maintenance therapy with rituximab, IgG levels remain essentially constant. Serious infections were rare.

Huo, X., X. Zhang, C. Yu, E. Cheng, Q. Zhang, K. B. Dunbar, T. H. Pham, J. P. Lynch, D. H. Wang, R. S. Bresalier, S. J. Spechler and R. F. Souza (2017). “Aspirin prevents nf-kappab activation and cdx2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with barrett’s oesophagus.” Gut: Apr [Epub ahead of print].

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OBJECTIVE: In previous studies using oesophageal squamous cells from patients with Barrett’s oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett’s oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. DESIGN: We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IkappaB-NF-kappaB-PKAc complex activation, p65 NF-kappaB subunit function, and CDX2 expression. RESULTS: In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H2O2, which activated the IkappaB-NF-kappaB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IkappaB and p65 and greater NF-kappaB transcriptional activity than NES-G cells, indicating greater IkappaB-NF-kappaB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IkappaB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. CONCLUSIONS: Differences between NES-B and NES-G cells in NF-kappaB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett’s oesophagus while others do not, and why aspirin might protect against development of Barrett’s oesophagus.

Kron, I. L., D. J. LaPar, M. A. Acker, D. H. Adams, G. Ailawadi, S. F. Bolling, J. W. Hung, D. S. Lim, M. J. Mack, P. T. O’Gara, M. K. Parides and J. D. Puskas (2017). “2016 update to the american association for thoracic surgery (aats) consensus guidelines: Ischemic mitral valve regurgitation.” J Thorac Cardiovasc Surg 153(5): e97-e114.

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The objective of this project was to provide an update to the previously published consensus 2015 The American Association for Thoracic Surgery (AATS) evidence-based guidelines for the management of ischemic mitral regurgitation (IMR).

Koch, D. G., J. L. Speiser, V. Durkalski, R. J. Fontana, T. Davern, B. McGuire, R. T. Stravitz, A. M. Larson, I. Liou, O. Fix, M. L. Schilsky, T. McCashland, J. E. Hay, N. Murray, O. S. Shaikh, D. Ganger, A. Zaman, S. B. Han, R. T. Chung, R. S. Brown, S. Munoz, K. R. Reddy, L. Rossaro, R. Satyanarayana, A. J. Hanje, J. Olson, R. M. Subramanian, C. Karvellas, B. Hameed, A. H. Sherker, W. M. Lee and A. Reuben (2017). “The natural history of severe acute liver injury.” Am J Gastroenterol: Apr [Epub ahead of print].

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OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)>/=2.0 and alanine aminotransferase (ALT)>/=10 x elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR>/=2.0, ALT>/=10x elevated, and bilirubin>/=3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.