Physician Wellness in Academic Cardiovascular Medicine: A Scientific Statement From the American Heart Association.

Academic medicine as a practice model provides unique benefits to society. Clinical care remains an important part of the academic mission; however, equally important are the educational and research missions. More specifically, the sustainability of health care in the United States relies on an educated and expertly trained physician workforce directly provided by academic medicine models. Similarly, the research charge to deliver innovation and discovery to improve health care and to cure disease is key to academic missions. Therefore, to support and promote the growth and sustainability of academic medicine, attracting and engaging top talent from fellows in training and early career faculty is of vital importance. However, as the health care needs of the nation have risen, clinicians have experienced unprecedented demand, and individual wellness and burnout have been examined more closely. Here, we provide a close look at the unique drivers of burnout in academic cardiovascular medicine and propose system-level and personal interventions to support individual wellness in this model.

RECK suppresses interleukin-17/TRAF3IP2-mediated MMP-13 activation and human aortic smooth muscle cell migration and proliferation.

Sustained inflammation and matrix metalloproteinase (MMP) activation contribute to vascular occlusive/proliferative disorders. Interleukin-17 (IL-17) is a proinflammatory cytokine that signals mainly via TRAF3 Interacting Protein 2 (TRAF3IP2), an upstream regulator of various critical transcription factors, including AP-1 and NF-κB. Reversion inducing cysteine rich protein with kazal motifs (RECK) is a membrane-anchored MMP inhibitor. Here we investigated whether IL-17A/TRAF3IP2 signaling promotes MMP-13-dependent human aortic smooth muscle cell (SMC) proliferation and migration, and determined whether RECK overexpression blunts these responses. Indeed, IL-17A treatment induced (a) JNK, p38 MAPK, AP-1, NF-κB, and CREB activation, (b) miR-21 induction, (c) miR-27b and miR-320 inhibition, (d) MMP-13 expression and activation, (e) RECK suppression, and (f) SMC migration and proliferation, all in a TRAF3IP2-dependent manner. In fact, gain of TRAG3IP2 function, by itself, induced MMP-13 expression and activation, and RECK suppression. Furthermore, treatment with recombinant MMP-13 stimulated SMC migration in part via ERK activation. Importantly, RECK gain-of-function attenuated MMP-13 activity without affecting its mRNA or protein levels, and inhibited IL-17A- and MMP-13-induced SMC migration. These results indicate that increased MMP-13 and decreased RECK contribute to IL-17A-induced TRAF3IP2-dependent SMC migration and proliferation, and suggest that TRAF3IP2 inhibitors or RECK inducers have the potential to block the progression of neointimal thickening in hyperplastic vascular diseases.

TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart.

Persistent inflammation promotes development and progression of heart failure (HF). TWEAK (TNF-Related WEAK Inducer Of Apoptosis), a NF-κB- and/or AP-1-responsive proinflammatory cytokine that signals via TWEAK receptor (TWEAKR), is expressed at high levels in human and preclinical models of HF. Since the adapter molecule TRAF3IP2 (TRAF3 Interacting Protein 2) is an upstream regulator of various proinflammatory pathways, including those activated by NF-κB and AP-1, we hypothesized that targeting TRAF3IP2 inhibits TWEAK-induced proinflammatory and pro-fibrotic responses in vitro and in vivo. Consistent with the hypothesis, forced expression of TRAF3IP2 upregulated TWEAK and its receptor expression in cultured adult mouse cardiac fibroblasts (CF). Further, exogenous TWEAK upregulated TRAF3IP2 expression in a time- and dose-dependent manner, suggesting a positive-feedback regulation of TRAF3IP2 and TWEAK. TWEAK also promoted TRAF3IP2 nuclear translocation. Confirming its critical role in TWEAK signaling, silencing TRAF3IP2 inhibited TWEAK autoregulation, TWEAKR upregulation, p38 MAPK, NF-κB and AP-1 activation, inflammatory cytokine expression, MMP and TIMP1 activation, collagen expression and secretion, and importantly, proliferation and migration. Recapitulating these in vitro results, continuous infusion of TWEAK for 7 days increased systolic blood pressure (SBP), upregulated TRAF3IP2 expression, activated p38 MAPK, NF-κB and AP-1, induced the expression of multiple proinflammatory and pro-fibrotic mediators, and interstitial fibrosis in hearts of wild type mice. These proinflammatory and pro-fibrotic changes occurred in conjunction with myocardial hypertrophy and contractile dysfunction. Importantly, genetic ablation of TRAF3IP2 inhibited these TWEAK-induced adverse cardiac changes independent of increases in SBP, indicating that TRAF3IP2 plays a causal role, and thus a therapeutic target, in chronic inflammatory and fibro-proliferative diseases.

TRAF3IP2 mediates high glucose-induced endothelin-1 production as well as endothelin-1-induced inflammation in endothelial cells.

Hyperglycemia-induced production of endothelin (ET)-1 is a hallmark of endothelial dysfunction in diabetes. Although the detrimental vascular effects of increased ET-1 are well known, the molecular mechanisms regulating endothelial synthesis of ET-1 in the setting of diabetes remain largely unidentified. Here, we show that adapter molecule TRAF3 interacting protein 2 (TRAF3IP2) mediates high glucose-induced ET-1 production in endothelial cells and ET-1-mediated endothelial cell inflammation. Specifically, we found that high glucose upregulated TRAF3IP2 in human aortic endothelial cells, which subsequently led to activation of JNK and IKKß. shRNA-mediated silencing of TRAF3IP2, JNK1, or IKKß abrogated high-glucose-induced ET-converting enzyme 1 expression and ET-1 production. Likewise, overexpression of TRAF3IP2, in the absence of high glucose, led to activation of JNK and IKKß as well as increased ET-1 production. Furthermore, ET-1 transcriptionally upregulated TRAF3IP2, and this upregulation was prevented by pharmacological inhibition of ET-1 receptor B using BQ-788, or inhibition of NADPH oxidase-derived reactive oxygen species using gp91ds-tat and GKT137831. Notably, we found that knockdown of TRAF3IP2 abolished ET-1-induced proinflammatory and adhesion molecule (IL-1ß, TNF-α, monocyte chemoattractant protein 1, ICAM-1, VCAM-1, and E-selectin) expression and monocyte adhesion to endothelial cells. Finally, we report that TRAF3IP2 is upregulated and colocalized with CD31, an endothelial marker, in the aorta of diabetic mice. Collectively, findings from the present study identify endothelial TRAF3IP2 as a potential new therapeutic target to suppress ET-1 production and associated vascular complications in diabetes. NEW & NOTEWORTHY This study provides the first evidence that the adapter molecule TRAF3 interacting protein 2 mediates high glucose-induced production of endothelin-1 by endothelial cells as well as endothelin-1-mediated endothelial cell inflammation. The findings presented herein suggest that TRAF3 interacting protein 2 may be an important therapeutic target in diabetic vasculopathy characterized by excess endothelin-1 production.

Glycemic control by the SGLT2 inhibitor empagliflozin decreases aortic stiffness, renal resistivity index and kidney injury.

BACKGROUND: Arterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db). MATERIALS/METHODS: Ten-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n = 17), untreated db/db (DbC, n = 19) and EMPA-treated db/db mice (DbE, n = 19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg-1 day-1, and fed for 5 weeks, initiated at 11 weeks of age. RESULTS: Compared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression of "reversion inducing cysteine rich protein with Kazal motifs" (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells. CONCLUSIONS: Empagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression.

Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo.

The overall goals of this study were to investigate whether metformin exerts anti-fibrotic effects in aldosterone (Aldo)+salt-treated wild type mouse hearts, and determine the underlying molecular mechanisms in isolated adult cardiac fibroblasts (CF). In vitro, Aldo induced CF activation, migration, and proliferation, and these effects were inhibited by metformin. Further, Aldo induced PPM1A (Protein Phosphatase Magnesium Dependent 1A) activation and inhibited AMPK phosphorylation. At a pharmacologically relevant concentration, metformin restored AMPK activation, and inhibited Aldo-induced Nox4/H2O2-dependent TRAF3IP2 induction, pro-inflammatory cytokine expression, and CF migration and proliferation. Further, metformin potentiated the inhibitory effects of spironolactone, a mineralocorticoid receptor antagonist, on Aldo-induced collagen expression, and CF migration and proliferation. These results were recapitulated in vivo, where metformin reversed Aldo+salt-induced oxidative stress, suppression of AMPK activation, TRAF3IP2 induction, pro-inflammatory cytokine expression, and cardiac fibrosis, without significantly modulating systolic blood pressure. These in vitro and in vivo data indicate that metformin has the potential to reduce adverse cardiac remodeling in hypertensive heart disease.

Managing Career Transitions in Cardiothoracic Surgery.

Transitions during a career in cardiothoracic surgery include transition to practice following residency, multiple transitions over the course of the career, and transition to retirement. Each carries some degree of uncertainty and stress, and early preparation for each transition is key to success. A clear understanding of both professional and personal goals drives decisions and choices along the course of a career. It is crucial to seek legal counsel with expertise in physician employment contracts. Developing collegial and collaborative relationships should be a focus throughout one's career. This article outlines the key elements to successful career progression.

Implementation of entrustable professional activities in multiple surgical residencies: A quality improvement approach.

BACKGROUND: The COVID-19 pandemic decreased the operative case volume for surgical residents. Our institution implemented Entrustable Professional Activities (EPAs) in all core surgical training programs to document the competency of graduating residents. Continuation of this project aimed to improve implementation. METHODS: This project occurred at a large academic center with eight surgical specialties during the 2020-21 (Year 1) and 2021-22 (Year 2) academic years. Each specialty chose five EPAs, and residents were asked to obtain three micro-assessments per EPA. After the initial pilot year, program directors were surveyed regarding perceptions of EPA utility and barriers to implementation. RESULTS: Seventy senior residents completed 732/906 (80.8%) micro-assessments. Of these, 99.6% were deemed practice ready. Total micro-assessment completion rates in four specialties, four specific EPAs (including one EPA identified "at risk" due to the COVID-19 pandemic), and overall were significantly higher in Year 2 than Year 1 (p â€‹< â€‹0.05) CONCLUSIONS: Implementing EPAs in all core surgical specialties at an institution is achievable, though expectedly initially imperfect. An ongoing quality collaborative initiative focused on barriers to implementation can improve completion rates.

Down to the wire: tricuspid stenosis in the setting of multiple pacing leads.

Tricuspid stenosis in the setting of endocardial pacing leads is a rare entity, attributed to infection or lead malposition. We report the case of a 37-year-old man without these risk factors, who presented with new onset severe tricuspid stenosis in the setting of multiple chronic pacing leads.

Clinical Exposure to Cardiothoracic Surgery for Medical Students and General Surgery Residents.

BACKGROUND: The introduction of integrated 6-year cardiothoracic surgery (CTS) residency programs has shifted recruitment efforts to encompass not only general surgery (GS) residents, but also medical students. OBJECTIVE: The aim of this paper is to assess medical student and GS resident clinical exposure to CTS. DESIGN: Data from the Association of American Medical Colleges Visiting Student Application Service and the Accreditation Council for Graduate Medical Education Case Log Reports were collected from 2010 to 2017 and 2010 to 2018, respectively. The data extracted included medical students who applied and received an offer for elective rotations and the cases performed as a GS resident. RESULTS: A mean of 95 ± 28.5 medical students applied for CTS rotations annually and the applicants for CTS rotations increased by an average of 11.8% per year. However, significantly less students received an offer compared to other specialties (53.4% CTS vs 74.1% GS, 79.3% plastic surgery, 86.3% urology, 85.7% otolaryngology, 88.6% neurological surgery, and 89.6% orthopedic surgery) (p < 0.001). GS residents performed a mean of 39.3 ± 0.8 CTS procedures during residency: 32.9 ± 1.0 performed as a junior resident and 6.3 ± 0.7 as a chief resident. Out of all CTS procedures, 7.3% were cardiac procedures, with rates increasing from 5.6% to 8.4% during the study period (p = 0.001). CONCLUSIONS: Elective rotation opportunities in CTS are high in demand for medical students while GS residents receive limited CTS exposure, especially cardiac cases. Increasing clinical opportunities in both groups will aid in recruiting young talent to the field.

Empagliflozin reduces high glucose-induced oxidative stress and miR-21-dependent TRAF3IP2 induction and RECK suppression, and inhibits human renal proximal tubular epithelial cell migration and epithelial-to-mesenchymal transition.

Proximal tubular epithelial cells (PTEC) in the S1 segment of the kidney abundantly express sodium-glucose co-transporters (SGLT) that play a critical role in whole body glucose homeostasis. We recently reported suppression of RECK (Reversion Inducing Cysteine Rich Protein with Kazal Motifs), a membrane anchored endogenous MMP inhibitor and anti-fibrotic mediator, in the kidneys of db/db mice, a model of diabetic kidney disease (DKD), as well as in high glucose (HG) treated human kidney proximal tubule cells (HK-2). We further demonstrated that empagliflozin (EMPA), an SGLT2 inhibitor, reversed these effects. Little is known regarding the mechanisms underlying RECK suppression under hyperglycemic conditions, and its rescue by EMPA. Consistent with our previous studies, HG (25 mM) suppressed RECK expression in HK-2 cells. Further mechanistic investigations revealed that HG induced superoxide and hydrogen peroxide generation, oxidative stress-dependent TRAF3IP2 upregulation, NF-κB and p38 MAPK activation, inflammatory cytokine expression (IL-1ß, IL-6, TNF-α, and MCP-1), miR-21 induction, MMP2 activation, and RECK suppression. Moreover, RECK gain-of-function inhibited HG-induced MMP2 activation and HK-2 cell migration. Similar to HG, advanced glycation end products (AGE) induced TRAF3IP2 and suppressed RECK, effects that were inhibited by EMPA. Importantly, EMPA treatment ameliorated all of these deleterious effects, and inhibited epithelial-to-mesenchymal transition (EMT) and HK-2 cell migration. Collectively, these findings indicate that hyperglycemia and associated AGE suppress RECK expression via oxidative stress/TRAF3IP2/NF-κB and p38 MAPK/miR-21 induction. Furthermore, these results suggest that interventions aimed at restoring RECK or inhibiting SGLT2 have the potential to treat kidney inflammatory response/fibrosis and nephropathy under chronic hyperglycemic conditions, such as DKD.

Minocycline reverses IL-17A/TRAF3IP2-mediated p38 MAPK/NF-κB/iNOS/NO-dependent cardiomyocyte contractile depression and death.

Minocycline, an FDA-approved second-generation semisynthetic tetracycline, exerts antioxidant, anti-apoptotic and anti-inflammatory effects, independent of its antimicrobial properties. Interleukin (IL)-17A is an immune and inflammatory mediator, and its sustained induction is associated with various cardiovascular diseases. Here we investigated (i) whether IL-17A induces cardiomyocyte contractile depression and death, (ii) whether minocycline reverses IL-17A's negative inotropic effects and (iii) investigated the underlying molecular mechanisms. Indeed, treatment with recombinant mouse IL-17A impaired adult cardiomyocyte contractility as evidenced by a 34% inhibition in maximal velocity of shortening and relengthening after 4 h (P < .01). Contractile depression followed iNOS induction at 2 h (2.13-fold, P < .01) and NO generation at 3 h (3.71-fold, P <.01). Further mechanistic investigations revealed that IL-17A-dependent induction of iNOS occurred via TRAF3IP2, TRAF6, TAK1, NF-κB, and p38MAPK signaling. 1400 W, a highly specific iNOS inhibitor, suppressed IL-17A-induced NO generation and contractile depression, where as the NO donors SNAP and PAPA-NONOate both suppressed cardiomyocyte contractility. IL-17A also stimulated cardiomyocyte IL-1ß and TNF-α secretion, however, their neutralization failed to modulate IL-17A-mediated contractile depression or viability. Further increases of IL-17A concentration and the duration of exposure enhanced IL-1ß and TNF-α secreted levels, buthad no impact on adult cardiomyocyte viability. However, when combined with pathophysiological concentrations of IL-1ß or TNF-α, IL-17A promoted adult cardiomyocyte death. Importantly, minocycline blunted IL-17A-mediated deleterious effects, indicating its therapeutic potential in inflammatory cardiac diseases.

Diagnostic techniques in thoracic trauma.

Diagnosis of thoracic injury begins with a history of events and examination of the patient. Appropriate radiographic studies will be dictated by the findings on history and physical. Procedural examinations, such as endoscopy or angiography, may also be needed for accurate diagnosis.

Critical primary survey injuries.

The primary survey as established by the advanced trauma life support protocol includes a directed history and physical exam aimed at the rapid diagnosis of life-threatening thoracic injuries. Most of these injuries can and should be found and treated during the initial evaluation of the patient without the need for additional diagnostic studies. In this article we review the role of the primary survey in the diagnosis and treatment of major thoracic injuries.

Nina Starr Braunwald's Career, Legacy, and Awards: Results of a Survey of The Thoracic Surgery Foundation Award Recipients.

The legacy of Nina Starr Braunwald lives on in her innovations, clearing a path for women in cardiothoracic surgery, and in the lives of those she has trained or supported. As one of the early pioneers in cardiac surgery, she represents what is excellent in our profession. The Braunwald family has donated to The Thoracic Surgery Foundation in the form of Research Awards, and a survey was conducted to determine the career paths of recipients since the first award in 1993.