Research Spotlight

Packer, M. and McMurray, J.J.V. (2021). “Rapid Evidence-Based Sequencing of Foundational Drugs for Heart Failure and a Reduced Ejection Fraction.” Eur J Heart Fail Mar 11. [Epub ahead of print].

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Foundational therapy for heart failure and a reduced ejection fraction consists of a combination of an angiotensin receptor neprilysin inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor. However, the conventional approach to the implementation is based on a historically-driven sequence that is not strongly evidence-based, typically requires ≥6 months, and frequently lead to major gaps in treatment. We propose a rapid sequencing strategy that is based on four principles. First, since drugs act rapidly to reduce morbidity and mortality, patients should be started on all four foundational treatments within 2-4 weeks. Second, since the efficacy of each foundational therapy is independent of treatment with the other drugs, priority can be determined by considerations of relative efficacy, safety and ease-of-use. Third, low starting doses of foundational drugs have substantial therapeutic benefits, and achievement of low doses of all four classes of drugs should take precedence over uptitration to target doses. Fourth, since drugs can influence the tolerability of other foundational agents, sequencing can be based on whether agents started earlier can enhance the safety of agents started simultaneously or later in the sequence. We propose an accelerated 3-step approach, which consists of the simultaneous initiation of a beta-blocker and an SGLT2 inhibitor, followed 1-2 weeks later by the initiation of sacubitril/valsartan, and 1-2 weeks later by a mineralocorticoid receptor antagonist. The latter two steps can be reordered or compressed depending on patient circumstances. Rapid sequencing is a novel evidence-based strategy that has the potential to dramatically improve the implementation of treatments that reduce the morbidity and mortality of patients with heart failure and a reduced ejection fraction.

Roberts, W.C., Kietzman, A.T. and Rao, P.K. (2021). “Malignant Ventricular Tachycardia, Ventricular Wall Ablation, and Orthotopic Heart Transplantation.” Am J Cardiol Mar 19;S0002-9149(21)00262-9. [Epub ahead of print].

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Described herein are 3 patients with refractory ventricular tachycardia and one or more unsuccessful ablation procedures finally leading to orthotropic heart transplantation (OHT). The latter procedure allowed examination of the ventricular ablation sites, an unusual opportunity reported previously in few patients (all case reports). The acute ablation lesions are unique, with necrosis of the myocardial fibers adjacent to the endocardium and encircled by layers of extravasated erythrocytes in the deeper myocardial wall. All 3 patients returned to normal activities following the OHT.

Ribo, S., Sánchez-Infantes, D., Martinez-Guino, L., García-Mantrana, I., Ramon-Krauel, M., Tondo, M., Arning, E., Nofrarías, M., Osorio-Conles, Ó., Fernández-Pérez, A., González-Torres, P., Cebrià, J., Gavaldà-Navarro, A., Chenoll, E., Isganaitis, E., Villarroya, F., Vallejo, M., Segalés, J., Jiménez-Chillarón, J.C., Bottiglieri, T., Demerath, E.W., Fields, D.A., Collado, M.C. and Lerin, C. (2021). “Increasing breast milk betaine modulates Akkermansia abundance in mammalian neonates and improves long-term metabolic health.” Sci Transl Med 13(587).

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Accelerated postnatal growth is a potentially modifiable risk factor for future obesity. To study how specific breast milk components contribute to early growth and obesity risk, we quantified one-carbon metabolism-related metabolites in human breast milk and found an inverse association between milk betaine content and infant growth. This association was replicated in an independent and geographically distinct cohort. To determine the potential role of milk betaine in modulating offspring obesity risk, we performed maternal betaine supplementation experiments in mice. Higher betaine intake during lactation increased milk betaine content in dams and led to lower adiposity and improved glucose homeostasis throughout adulthood in mouse offspring. These effects were accompanied by a transient increase in Akkermansia spp. abundance in the gut during early life and a long-lasting increase in intestinal goblet cell number. The link between breast milk betaine and Akkermansia abundance in the gut was also observed in humans, as infants exposed to higher milk betaine content during breastfeeding showed higher fecal Akkermansia muciniphila abundance. Furthermore, administration of A. muciniphila to mouse pups during the lactation period partially replicated the effects of maternal breast milk betaine, including increased intestinal goblet cell number, lower adiposity, and improved glucose homeostasis during adulthood. These data demonstrate a link between breast milk betaine content and long-term metabolic health of offspring.

Putman, J.M., Zhang, L., Gregg, A.R., Testa, G. and Johannesson, L. (2021). “Clinical pregnancy rates and experience with in vitro fertilization after uterus transplantation: Dallas Uterus Transplant Study.” Am J Obstet Gynecol Mar 12;S0002-9378(21)00165-4. [Epub ahead of print].

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BACKGROUND: The clinical pregnancy rates among patients with uterus transplantation have been reported by only a limited number of centers, and those centers have not used preimplantation genetic testing for aneuploidy in their protocol. OBJECTIVE: This study examined clinical pregnancy rates among women with absolute uterine-factor infertility undergoing in vitro fertilization using good-quality, expanded-blastocyst-stage, euploid embryos after uterus transplantation. STUDY DESIGN: This cohort observational study involved 20 women who underwent uterus transplantation over 3 years. Notably, 14 of these patients had successful transplants and were followed prospectively for a median of 14.1 months (range, 11-34.8 months). In vitro fertilization was performed before subjects underwent uterus transplantation, and good-quality expanded-blastocyst-stage euploid embryos were obtained and frozen for future embryo transfer. Interventions consisted of in vitro fertilization, preimplantation genetic testing for aneuploidy, uterus transplantation, and frozen embryo transfer. RESULTS: All 14 subjects with successful transplants underwent single embryo transfer of a warmed, good-quality, euploid, expanded blastocyst and had at least 1 documented clinical pregnancy within the uterus. In 71.4%, the first embryo transfer resulted in clinical pregnancy. The median time from successful uterus transplantation to first embryo transfer was 4.5 months; from successful uterus transplantation to first clinical pregnancy, 7.3 months; and from successful uterus transplantation to first live birth, 14.1 months. A total of 13 live births have occurred in 12 subjects. CONCLUSION: Women with absolute uterine-factor infertility who have surgically successful uterus transplantation and in vitro fertilization using preimplantation genetic testing for aneuploidy can achieve high clinical pregnancy rates. We have reduced the time interval from uterus transplantation to embryo transfer by at least 50% and the interval from uterus transplantation to clinical pregnancy by >6 months compared with previous studies. We believe our approach may shorten the time from transplant to clinical pregnancy and therefore decrease patient exposure to immunosuppressant therapies.

Pennington, M.L., Dupree, J., Coe, E., Ostiguy, W., Kimbrel, N.A., Meyer, E.C. and Gulliver, S.B. (2021). “Working near a supervised injection facility: A qualitative study of perspectives of firefighter-emergency medical responders.” Am J Ind Med 64(4): 296-300.

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BACKGROUND: While firefighter-emergency medical responders (FF-EMR) are important stakeholders in cities considering the implementation of a supervised injection facility (SIF), there is little information on perspectives of first responders who serve these communities. The aim of the present study was to identify FF-EMR perspectives on working near a SIF. METHODS: FF-EMRs from Vancouver Fire and Rescue Services completed an online survey that queried participant perspectives on working near a SIF. RESULTS: Four main themes were identified: positive effects, negative effects, duration of assignment, and sense of duty. Similar percentages of first responders reported positive (22.2%) and negative aspects (25.9%) of working near the SIF, while some (18.5%) indicated preference for a short-term assignment to the SIF area. FF-EMRs most commonly described a sense of duty (35.2%). CONCLUSIONS: To our knowledge, our study is the first to identify FF-EMR perspectives related to work near a SIF. Perspectives and concerns of first responders should be considered in policy debates about implementation of new SIFs to guarantee an adequately-prepared first responder workforce.