Research Spotlight

McCullough, P. A., G. David, T. M. Todoran, E. S. Brilakis, M. P. Ryan and C. Gunnarsson (2017). “Iso-osmolar contrast media and adverse renal and cardiac events after percutaneous cardiovascular intervention.” J Comp Eff Res: 2017 Nov [Epub ahead of print].

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AIM: To assess the relationship between type of contrast media (CM), iso-osmolar contrast media (IOCM) or low-osmolar contrast media (LOCM), and major adverse renal and cardiovascular events (MARCE). MATERIALS & METHODS: Coronary or peripheral angioplasty visits were stratified into CM cohorts: IOCM or LOCM. Multivariable regression analysis used hospital fixed effects to assess the relationship between MARCE events and type of CM. RESULTS: Among 333,533 visits (357 hospitals), the incidence of MARCE was 7.41%. After controlling for observable and unobservable time invariant within-hospital characteristics, administration of IOCM versus LOCM was associated with a 0.69% absolute and 9.32% relative risk reduction in MARCE rate. CONCLUSION: Our study indicates that as compared with LOCM, IOCM may be associated with reduction of MARCE events in coronary or peripheral angioplasty patients.

Angelieri, F., L. Franchi, L. H. S. Cevidanes, J. R. Goncalves, M. Nieri, L. M. Wolford and J. A. McNamara, Jr. (2017). “Cone beam computed tomography evaluation of midpalatal suture maturation in adults.” Int J Oral Maxillofac Surg 46(12): 1557-1561.

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The aim of this study was to evaluate midpalatal suture maturation in adults, as observed in cone beam computed tomography (CBCT) images. CBCT scans from 78 subjects (64 female and 14 male, age range from 18 to 66 years) were evaluated. Midpalatal suture maturation was verified on the central cross-sectional axial slice in the superior-inferior dimension of the palate, using methods validated previously. Intra-examiner agreement was analyzed by weighted kappa test. Multinomial logistic regression was used to test whether sex and chronological age (adults <30 years or >/=30 years) could be used as a predictor for the maturational stages of the midpalatal suture. The majority of the adults presented a fused midpalatal suture in the palatine (stage D) and/or maxillary bones (stage E). However, the midpalatal suture was not fused in 12% of the subjects. Sex and chronological age were not significant predictors of the maturational stages of the midpalatal suture. The individual assessment of midpalatal suture maturation by way of CBCT images may provide reliable information critical to making the clinical decision between rapid maxillary expansion and surgically assisted rapid maxillary expansion for the treatment of maxillary atresia in adults.

Mogensen, U. M., L. Kober, P. S. Jhund, A. S. Desai, M. Senni, S. L. Kristensen, A. Dukat, C. H. Chen, F. Ramires, M. P. Lefkowitz, M. F. Prescott, V. C. Shi, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. Packer and J. J. V. McMurray (2017). “Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in paradigm-hf.” Eur J Heart Fail: 2017 Nov [Epub ahead of print].

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AIMS: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF. METHODS AND RESULTS: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1-Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA >/=8.6 mg/dL) compared with Q1 (<5.4 mg/dL) were younger (62.8 vs. 64.2 years), more often male (88.7% vs. 63.1%), had lower systolic blood pressure (119 vs. 123 mmHg), lower eGFR (57.4 vs. 76.6 mL/min/1.73 m(2) ), and greater diuretic use. Higher SUA was associated with a higher risk of the primary outcome (adjusted hazard ratios) Q5 vs. Q1 = 1.28 [95% confidence intervals (1.09-1.50), P = 0.003], cardiovascular death [1.44 (1.11-1.77), P = 0.001], HF hospitalization [1.37 (1.11-1.70), P = 0.004], and all-cause mortality [1.36 (1.13-1.64), P = 0.001]. Compared with enalapril, sacubitril/valsartan reduced SUA by 0.24 (0.17-0.32) mg/dL over 12 months (P < 0.0001). Sacubitril/valsartan improved outcomes, irrespective of SUA concentration. CONCLUSION: Serum uric acid concentration was an independent predictor of worse outcomes after multivariable adjustment in patients with HFrEF. Compared with enalapril, sacubitril/valsartan reduced SUA and improved outcomes irrespective of SUA.

Moon, S. H., X. Liu, A. M. Cedars, K. Yang, M. A. Kiebish, S. M. Joseph, J. Kelley, C. M. Jenkins and R. W. Gross (2017). “Heart failure-induced activation of phospholipase ipla2gamma generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore.” J Biol Chem: 2017 Nov [Epub ahead of print].

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Congestive heart failure typically arises from cardiac myocyte necrosis/apoptosis, associated with the pathological opening of the mitochondrial permeability transition pore (mPTP). mPTP opening decreases the mitochondrial membrane potential leading to the activation of Ca(2+)-independent phospholipase A2gamma (iPLA2gamma) and the production of downstream toxic metabolites. However, the array of enzymatic mediators and the exact chemical mechanisms responsible for modulating myocardial mPTP opening remain unclear. Herein, we demonstrate that human heart failure activates specific myocardial mitochondrial phospholipases that increase Ca(2+)-dependent production of toxic hydroxyeicosatetraenoic acids (HETEs) and attenuate the activity of phospholipases that promote the synthesis of protective epoxyeicosatrienoic acids (EETs). Mechanistically, HETEs activated the Ca(2+)-induced opening of the mPTP in failing human myocardium, and highly selective pharmacological blockade of either iPLA2gamma or lipoxygenases attenuated mPTP opening in failing hearts. In contrast, pharmacological inhibition of cytochrome P450 epoxygenases opened the myocardial mPTP in human heart mitochondria. Remarkably, the major mitochondrial phospholipase responsible for Ca(2+)-activated release of arachidonic acid (AA) in mitochondria from non-failing hearts was calcium-dependent phospholipase A2zeta (cPLA2zeta) identified by sequential column chromatographies and activity-based protein profiling. In contrast, iPLA2gamma predominated in failing human myocardium. Stable isotope kinetics revealed that in non-failing human hearts, cPLA2zeta metabolically channels arachidonic acid into EETs, whereas, in failing hearts, increased iPLA2gamma activity channels AA into toxic HETEs. These results mechanistically identify the sequelae of pathological remodeling of human mitochondrial phospholipases in failing myocardium. This remodeling metabolically channels AA into toxic HETEs promoting mPTP opening, which induces necrosis/apoptosis leading to further progression of heart failure.

Myers, R. M., B. T. Hill, B. E. Shaw, S. Kim, H. R. Millard, M. Battiwalla, N. S. Majhail, D. Buchbinder, H. M. Lazarus, B. N. Savani, M. E. D. Flowers, A. D’Souza, M. J. Ehrhardt, A. Langston, J. A. Yared, R. J. Hayashi, A. Daly, R. F. Olsson, Y. Inamoto, A. K. Malone, Z. DeFilipp, S. P. Margossian, A. B. Warwick, S. Jaglowski, A. Beitinjaneh, H. Fung, K. A. Kasow, D. I. Marks, J. Reynolds, K. Stockerl-Goldstein, B. Wirk, W. A. Wood, M. Hamadani and P. Satwani (2017). “Long-term outcomes among 2-year survivors of autologous hematopoietic cell transplantation for hodgkin and diffuse large b-cell lymphoma.” Cancer: 2017 Nov [Epub ahead of print].

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BACKGROUND: Autologous hematopoietic cell transplantation (auto-HCT) is a standard therapy for relapsed classic Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL); however, long-term outcomes are not well described. METHODS: This study analyzed survival, nonrelapse mortality, late effects, and subsequent malignant neoplasms (SMNs) in 1617 patients who survived progression-free for >/=2 years after auto-HCT for cHL or DLBCL between 1990 and 2008. The median age at auto-HCT was 40 years; the median follow-up was 10.6 years. RESULTS: The 5-year overall survival rate was 90% (95% confidence interval [CI], 87%-92%) for patients with cHL and 89% (95% CI, 87%-91%) for patients with DLBCL. The risk of late mortality in comparison with the general population was 9.6-fold higher for patients with cHL (standardized mortality ratio [SMR], 9.6) and 3.4-fold higher for patients with DLBCL (SMR, 3.4). Relapse accounted for 44% of late deaths. At least 1 late effect was reported for 9% of the patients. A total of 105 SMNs were confirmed: 44 in the cHL group and 61 in the DLBCL group. According to a multivariate analysis, older age, male sex, a Karnofsky score < 90, total body irradiation (TBI) exposure, and a higher number of lines of chemotherapy before auto-HCT were risk factors for overall mortality in cHL. Risk factors in DLBCL were older age and TBI exposure. A subanalysis of 798 adolescent and young adult patients mirrored the outcomes of the overall study population. CONCLUSIONS: Despite generally favorable outcomes, 2-year survivors of auto-HCT for cHL or DLBCL have an excess late-mortality risk in comparison with the general population and experience an assortment of late complications.