The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character. In addition to antioxidant and detoxification genes, Nrf2 has been found to regulate genes participating in cell signaling, transcription, anabolic metabolism, autophagy, cell proliferation, extracellular matrix remodeling, and organ development, suggesting that Nrf2 governs damage resistance as well as wound repair and tissue remodeling. A long list of small molecules, most derived from natural products, have been characterized as Nrf2 inducers. These compounds disrupt Keap1-mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes. Recently alternative mechanisms driving Nrf2 protein increase have been revealed, including removal of Keap1 by autophagy due to p62/SQSTM1 binding, inhibition of βTrCP or Synoviolin/Hrd1-mediated ubiquitination of Nrf2, and de novo Nrf2 protein translation. We review here a large volume of literature reporting historical and recent discoveries about the function and regulation of Nrf2 gene. Multiple lines of evidence presented here support the potential of dialing up the Nrf2 pathway for cardiac protection in the clinic.

Objectives Despite evidence, frailty is not routinely assessed before cardiac surgery. We compared five brief frailty tests for predicting poor outcomes after aortic valve replacement and evaluated a strategy of performing comprehensive geriatric assessment (CGA) in screen‐positive patients. Design Prospective cohort study. Setting A single academic center. Participants Patients undergoing surgical aortic valve replacement (SAVR) (n = 91; mean age = 77.8 y) or transcatheter aortic valve replacement (TAVR) (n = 137; mean age = 84.5 y) from February 2014 to June 2017. Measurements Brief frailty tests (Fatigue, Resistance, Ambulation, Illness, and Loss of weight [FRAIL] scale; Clinical Frailty Scale; grip strength; gait speed; and chair rise) and a deficit‐accumulation frailty index based on CGA (CGA‐FI) were measured at baseline. A composite of death or functional decline and severe symptoms at 6 months was assessed. Results The outcome occurred in 8.8% (n = 8) after SAVR and 24.8% (n = 34) after TAVR. The chair rise test showed the highest discrimination in the SAVR (C statistic = .76) and TAVR cohorts (C statistic = .63). When the chair rise test was chosen as a screening test (≥17 s for SAVR and ≥23 s for TAVR), the incidence of outcome for screen‐negative patients, screen‐positive patients with CGA‐FI of .34 or lower, and screen‐positive patients with CGA‐FI higher than .34 were 1.9% (n = 1/54), 5.3% (n = 1/19), and 33.3% (n = 6/18) after SAVR, respectively, and 15.0% (n = 9/60), 14.3% (n = 3/21), and 38.3% (n = 22/56) after TAVR, respectively. Compared with routinely performing CGA, targeting CGA to screen‐positive patients would result in 54 fewer CGAs, without compromising sensitivity (routine vs targeted: .75 vs .75; P = 1.00) and specificity (.84 vs .86; P = 1.00) in the SAVR cohort; and 60 fewer CGAs with lower sensitivity (.82 vs.65; P = .03) and higher specificity (.50 vs .67; P < .01) in the TAVR cohort. Conclusions The chair rise test with targeted CGA may be a practical strategy to identify older patients at high risk for mortality and poor recovery after SAVR and TAVR in whom individualized care management should be considered. J Am Geriatr Soc 67:2031–2037, 2019

Misfolded immunoglobulin light chain proteins (LC) in light chain amyloidosis (AL) are toxic to vascular tissues. We tested the hypothesis that chaperone protein clusterin preserves endothelial function and cell survival during LC exposure. Methods LC (20 μg/mL) were given to human aortic endothelial cells (EC) for 24-hours and clusterin protein/gene expression and secretion were measured. DNA fragmentation was measured with/without recombinant clusterin (Clu, 300 ng/mL). Adipose arterioles (non-AL subjects) were tested for dilator responses to acetylcholine/papaverine at baseline and after 1-hour of LC±Clu. Results LC reduced EC clusterin secretion, protein and gene expression while increasing DNA fragmentation. Clu attenuated LC-induced DNA fragmentation and restored dilator response to acetylcholine (logEC50: control −7.05±0.2, LC+Clu −6.53±0.4, LC −4.28±0.7, p<0.05 vs. control, LC+Clu). Conclusions LC induced endothelial cell death and dysfunction while reducing clusterin protein/gene expression and secretion. Exogenous clusterin attenuated LC toxicity. This represents a new pathobiologic mechanism and therapeutic target for AL amyloidosis.

Pre-clerkship curricula of most Liaison Committee on Medical Education (LCME)-accredited medical schools are divided into blocks by organ system, leaving a significant amount of information susceptible to loss due to prolonged nonuse. We describe the implementation of a formal Spiral Curriculum that periodically revisits material from previous blocks. Learners were surveyed on receptivity to the curriculum across three graduating classes at a single medical school. Medical school graduate classes of 2020, 2021, and 2022 were surveyed at the end of their pre-clerkship years (2018–2020). The class of 2022 actually received the Spiraled Curriculum intervention, for which the authors created 500 board exam style multiple-choice questions, periodically administered via mandatory in-class sessions ranging from 10 to 20 questions reviewing content from previous blocks with designated expert faculty. Response rates were 36% ( n = 46), 45% ( n = 52), and 32% ( n = 40) for classes of 2020, 2021, and 2022, respectively. On a Likert scale (1 = strongly disagree, 5 = neutral, 10 = strongly agree), the classes of 2020, 2021, and 2022 provided statistically significant differences in their belief that a Spiraled Curriculum would/did help them retain information as 8.2 (SD 1.7), 8.2 (SD 2.2), and 5.0 (SD 3.0) ( n < 0.05). All classes endorsed neutral confidence in the existing pre-clerkship curriculum in themselves to prepare for United Stated Medical Licensing Examination (USMLE) Step 1, and in their retention of previous block material with no statistically significant differences between classes. USMLE Step 1 scores did not differ significantly between classes ( n = 0.21). Those who did not receive the Spiral Curriculum were highly receptive to it in theory, while those who actually received the intervention gave a neutral rating. Per survey comments, implementation of a Spiraling Curriculum would ideally be administered as either team-based or self-directed activities, and a Spiraling Curriculum may be difficult to implement in accelerated (18 month) pre-clerkship formats. Practice points Question: What is the receptivity of medical students to a formal Spiral curriculum that uses time-spaced repetition sessions of board exam style questions to revisit previous block content of their pre-clerkship years? Findings: In this single-center, quasi-experimental study, the two control group medical school classes had very positive theoretical reception to a Spiral curriculum proposal (rated 8 out of 10) while the class who actually received the Spiral curriculum provided a statistically significant lower neutral rating (rated 5 out of 10), citing preference for a team-based or self-directed format. Meaning: Medical students are strongly in favor of structured time-spaced repetition with board exam style questions to revisit pr...

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