Research Spotlight

Oliveros, E., E. T. Oni, A. Shahzad, A. Y. Kluger, K. B. Lo, J. Rangaswami and P. A. McCullough (2020). “Benefits and Risks of Continuing Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Antagonists, and Mineralocorticoid Receptor Antagonists during Hospitalizations for Acute Heart Failure.” Cardiorenal Med Feb 14:1-16. [Epub ahead of print].

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BACKGROUND: The renin-angiotensin-aldosterone axis plays a pivotal role in the pathophysiology of acute and chronic heart failure (HF) and represents an important target for guideline-directed medical therapy. SUMMARY: The use of appropriate directed medical therapies for inhibition of the renin-angiotensin-aldosterone axis in chronic HF has been the subject of several landmark clinical trials, with high levels of adherence exhibited in the outpatient setting. However, less clarity exists with respect to the initiation, continuation, and cessation of renin-angiotensin-aldosterone system inhibitors (RAASi) in the setting of acute HF and exacerbation of HF necessitating hospitalization. In this review, we summarize relevant aspects of the physiology of the renin-angiotensin-aldosterone axis in acute HF and during decongestion. We also summarize the available evidence for the risks and benefits of initiating and continuing RAASi in acute HF. Key Message: We offer a decision-making pathway for the use of RAASi in the setting of acute HF that would help guide the cardiologist and nephrologist caring for patients with acute HF and cardiorenal syndrome.

Nowak, A., U. Huynh-Do, P. A. Krayenbuehl, F. Beuschlein, R. Schiffmann and F. Barbey (2020). “Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort.” J Inherit Metab Dis 43(2): 326-333.

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Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by alpha-galactosidase A (alpha-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. The pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy in patients with amenable mutations. In this article, we investigate the proportion of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland. This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. Overall, 68% had the classic phenotype and 48% fulfilled the current amenability criteria. Migalastat was stopped in 2/11 (18%) patients: the only male classic patient, because of lack of efficacy based on lyso-Gb3 levels, and one patient with a benign variant. In males, the achieved enzyme activities in peripheral leucocytes under migalastat treatment differed from the activities in HEK-cells after incubation with migalastat (eg, 33% in PL vs 41% HEK-cells for p.F113L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238N). In this national cohort, we found a relatively high proportion of patients with amenable GLA mutations, which, however, had heterogeneous extent of amenability: the higher the residual alpha-Gal A activity, the higher the chaperone effect. Further studies are required to investigate the long-term benefits of migalastat therapy depending on the achieved enzyme activities in different amenable mutations.

Ngaage, L. M., S. Ike, A. Elegbede, C. J. Vercler, S. Gebran, F. Liang, E. M. Rada, C. Cooney, G. Brandacher, R. J. Redett, L. Johannesson and Y. M. Rasko (2020). “The changing paradigm of ethics in uterus transplantation: a systematic review.” Transpl Int 33(3): 260-269.

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The first uterus transplantation was performed in 2000. As key milestones are reached (long-lasting graft survival in 2011, and first birth from a transplanted womb in 2014), the ethical debate around uterus transplant evolves. We performed a systematic review of articles on uterus transplantation. Ethical themes were extracted and categorized according to four bioethical principles. Papers were divided into time periods separated by key events in uterus transplant history: Phase I (first technical achievement, 2002-2011), Phase II (clinical achievement, 2012-2014), and Phase III (after the first childbirth, 2015-2018). Eighty-one articles were included. The majority of ethics papers were published in Phase III (65%, P < 0.0001), that is after the first birth. Eighty percent of papers discussed nonmaleficence making it the most discussed principle. The first birth acted as a pivotal point: nonmaleficence was discussed by a lower proportion of articles (P = 0.0073), as was beneficence (P = 0.0309). However, discussion of justice increased to become the most discussed principle of the time period (P = 0.0085). The ethical debate surrounding uterus transplantation has evolved around landmark events that signify scientific progress. As safety and efficacy become evident, the focus of ethical debate shifts from clinical equipoise to socioeconomic challenges and equitable access to uterus transplantation.

Nakase-Richardson, R., M. N. Dahdah, E. Almeida, P. Ricketti, M. A. Silva, K. Calero, U. Magalang and D. J. Schwartz (2020). “Concordance Between Current AASM and CMS Scoring Criteria for Obstructive Sleep Apnea in Hospitalized Persons With TBI: A VA TBI Model System Study.” J Clin Sleep Med Feb 11. [Epub ahead of print].

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STUDY OBJECTIVES: To compare OSA, demographic, and TBI characteristics across the American Academy of Sleep Medicine (AASM) and Centers for Medicare and Medicare (CMS) scoring rules in moderate to severe TBI undergoing inpatient neurorehabilitation. METHODS: This is a secondary analysis from a prospective clinical trial of sleep apnea at six TBI Model System study sites (n=248). Scoring was completed by a centralized center using both the AASM and CMS criteria for OSA. Hospitalization and injury characteristics were abstracted from the medical record and demographics obtained by interview by trained research assistants using TBI Model System standard procedures. RESULTS: OSA was prevalent using the AASM (66%) and CMS (41.5%) criteria with moderate to strong agreement (weighted kappa = 0.64 (95%CI = 0.58, 0.70). Significant differences were observed for participants meeting AASM and CMS criteria (Concordant Group; CG) compared to those meeting criteria for AASM but not CMS (Discordant Group; DG). At AHI >/= 5, the DG (n=61) had lower Emergency Department Glasgow Coma Scale Scores consistent with greater injury severity (median 5 vs. 13, p = 0.0050), younger age (median 38 vs 58, p<0.0001), and lower BMI (median 24.8 vs 22.1, p = 0.0007) compared to the CG (n=103). At AHI >/= 15, female gender and but no other differences were noted possibly due to the smaller sample size. CONCLUSIONS: The underestimation of sleep apnea using CMS criteria is consistent with prior literature; however, this is the first study to report the impact of the criteria in persons with moderate to severe TBI during a critical stage of neural recovery. Management of comorbidities in TBI has become an increasing focus for optimizing TBI outcomes. Given the chronic morbidity after moderate to severe TBI, the impact of CMS policy for OSA diagnosis for persons with chronic disability and young age are considerable.

Menter, A., J. M. Gelfand, C. Connor, A. W. Armstrong, K. M. Cordoro, D. M. R. Davis, B. E. Elewski, K. B. Gordon, A. B. Gottlieb, D. H. Kaplan, A. Kavanaugh, M. Kiselica, D. Kivelevitch, N. J. Korman, D. Kroshinsky, M. Lebwohl, C. L. Leonardi, J. Lichten, H. W. Lim, N. N. Mehta, A. S. Paller, S. L. Parra, A. L. Pathy, E. F. Prater, R. S. Rahimi, R. N. Rupani, M. Siegel, B. Stoff, B. E. Strober, E. B. Tapper, E. B. Wong, J. J. Wu, V. Hariharan and C. A. Elmets (2020). “Joint Aad-Npf Guidelines Of Care For The Management Of Psoriasis With Systemic Non-Biological Therapies.” J Am Acad Dermatol Feb 21. [Epub ahead of print].

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Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately 2% of the world’s population. In this guideline, we focus the discussion on systemic, non-biologic medications for the treatment of this disease. We provide a detailed discussion of efficacy and safety for the most commonly used medications-including methotrexate, cyclosporine, and acitretin-and provide recommendations to assist prescribers in initiating and managing patients on these treatments. Additionally, we discuss newer therapies, including tofacitinib and apremilast, and briefly touch upon a number of other medications, including fumaric acid esters (used outside the US) and therapies that are no longer widely used for the treatment of psoriasis, i.e. hydroxyurea, leflunomide, mycophenolate mofetil, thioguanine, and tacrolimus.