Caveolar Compartmentalization of Pacemaker Signaling is Required for Stable Rhythmicity of Sinus Nodal Cells and is Disrupted in Heart Failure.

Background: Heart rhythm relies on complex interactions between electrogenic membrane proteins and intracellular Ca 2+ signaling in sinoatrial node (SAN) myocytes; however, mechanisms underlying the functional organization of proteins involved in SAN pacemaking and its structural foundation remain elusive. Caveolae are nanoscale, plasma membrane pits that compartmentalize various ion channels and transporters, including those involved in SAN pacemaking, via binding with the caveolin-3 scaffolding protein, but the precise role of caveolae in cardiac pacemaker function is unknown. Our objective was to determine the role of caveolae in SAN pacemaking and dysfunction (SND). Methods: Biochemical co-purification, in vivo electrocardiogram monitoring, ex vivo optical mapping, in vitro confocal Ca 2+ imaging, and immunofluorescent and electron microscopy analyses were performed in wild type, cardiac-specific caveolin-3 knockout, and 8-weeks post-myocardial infarction heart failure (HF) mice. SAN tissue samples from donor human hearts were used for biochemical studies. We utilized a novel 3-dimensional single SAN cell mathematical model to determine the functional outcomes of protein nanodomain-specific localization and redistribution in SAN pacemaking. Results: In both mouse and human SANs, caveolae compartmentalized HCN4, Ca v 1.2, Ca v 1.3, Ca v 3.1 and NCX1 proteins within discrete pacemaker signalosomes via direct association with caveolin-3. This compartmentalization positioned electrogenic sarcolemmal proteins near the subsarcolemmal sarcoplasmic reticulum (SR) membrane and ensured fast and robust activation of NCX1 by subsarcolemmal local SR Ca 2+ release events (LCRs), which diffuse across ∼15-nm subsarcolemmal cleft. Disruption of caveolae led to the development of SND via suppression of pacemaker automaticity through a 50% decrease of the L-type Ca 2+ current, a negative shift of the HCN current ( I f ) activation curve, and a 40% reduction of Na + /Ca 2+ -exchanger function, along with ∼2.3-times widening of the sarcolemma-SR distance. These changes significantly decreased the SAN depolarizing force, both during diastolic depolarization and upstroke phase, leading to bradycardia, sinus pauses, recurrent development of SAN quiescence, and significant increase in heart rate lability. Computational modeling, supported by biochemical studies, identified NCX1 redistribution to extra-caveolar membrane as the primary mechanism of SAN pauses and quiescence due to the impaired ability of NCX1 to be effectively activated by LCRs and trigger action potentials. HF remodeling mirrored caveolae disruption leading to NCX1-LCR uncoupling and SND. Conclusions: SAN pacemaking is driven by complex protein interactions within a nanoscale caveolar pacemaker signalosome. Disruption of caveolae leads to SND, potentially demonstrating a new dimension of SAN remodeling and providing a newly recognized target for therapy.

Outcomes of enhanced recovery protocols and tranexamic acid on double-incision versus periareolar gender-affirming mastectomy: A retrospective study of postoperative outcomes.

INTRODUCTION: The effects of enhanced recovery protocols and use of tranexamic acid (TXA) to reduce postoperative complications after periareolar and double-incision (DIM) gender-affirming mastectomies have not been previously described. We sought to evaluate the efficacy of our ERP including use of liposomal bupivacaine [Exparel] in these cases, assess the efficacy of TXA in reducing postoperative complications, and compare need for revisionary surgery between periareolar and DI mastectomy techniques. MATERIALS AND METHODS: A retrospective review from November 2017 to June 2022 was performed. Data were collected on patient demographics, operative data, and postoperative outcomes including complications and revisions. Morphine milligram equivalent was used to assess opioid use after surgery. RESULTS: Overall, 260 patients were included: 240 (92.3%) patients in the DI and 20 (7.7%) patients in the periareolar group. Thirty-five (7.3%) breasts in the DIM group and five (12.5%) breasts in the periareolar cohort developed complications (p = 0.220). Significantly more breasts in the periareolar cohort developed hematomas (12.5% vs. 2.9%, p = 0.011). Sixteen (3.3%) breasts in the DIM group developed seromas. Significantly more breasts in the periareolar group required revisionary surgery (15.0% vs. 5.2%, p = 0.025). Patients who received intraoperative liposomal bupivacaine [Exparel] had fewer opioids intraoperatively (p = 0.019) and at discharge (p < 0.001). Use of TXA did not affect rates of complications including hematoma or seroma. CONCLUSIONS: Overall, complication rates for periareolar and DIM are similar. However, the periareolar technique results in a significantly higher rate of hematomas and revisionary surgery. Use of intraoperative liposomal bupivacaine [Exparel] resulted in significantly lower opioid use. Lastly, use of topical TXA did not lower the risk of postoperative hematoma or seroma.

Optimize Your First Impression: A Comparison of the Aesthetic Websites of Private Practices and Academic Institutions.

BACKGROUND: An aesthetic surgery offering within academic programs has positive financial and educational implications. To compete with private practices, academic institutions must view their website as integral to patient recruitment. OBJECTIVE: This study examines the aesthetic surgery websites of academic and private practices to compare objective website characteristics. METHODS: Integrated plastic surgery programs with an aesthetic surgery website were matched with nearby private practices offering cosmetic surgery. Data was collected from websites, including information about procedures, media, surgeon characteristics, design, reputation, finances, and readability, and compared using Chi-square and T tests. RESULTS: The websites of 68 academic institutions (AP) and 68 location-matched private practices (PP) were examined. Fourteen (17.07%) programs did not have a website. Private practice websites provided information about a greater number of procedures (mean AP 21.82, PP 27.04, p = 0.013), preparation for surgery (AP 52.94%, PP 83.82%, p < 0.001), and expectations after surgery (AP 70.59%, PP 88.24%, p = 0.01). Board certification was listed more frequently for private practices (AP 87%, PP 98%, p = 0.01). Academic websites were more likely to discuss research (AP 76%, PP 57.35%, p = 0.02). There was no significant difference in the readability of AP and PP websites (mean SMOG AP 7.70, PP 7.19, p = 0.06). CONCLUSIONS: This work demonstrates a significant content gap between private and academic aesthetic websites and serves as an action item for institutions to enhance their online presence. In a field traditionally associated with high overhead costs, website modifications represent a cost-effective way for academic practices to increase their appeal in the cosmetic surgery market. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

To Decline or Accept: A Guide for Determining the Legitimacy of Academic Conference Invitations.

IMPORTANCE: After the rise of predatory journals characterized by false claims of legitimacy and a pay-to-publish model, similar "predatory conferences" have become increasingly common. The email inbox of an academic physician can be filled with daily announcements encouraging conference attendance, abstract submission, and often panel or keynote speaker invitations. It therefore becomes important for the plastic surgeon to be able to discern whether these invitations are from "predatory" conferences or legitimate career advancement opportunities, especially early in practice. OBJECTIVE: To aid the invited physician in determining the legitimacy of a conference, we aimed to characterize objective features of conferences for which email invitations have been received and use this information to build a decision-making guide. DESIGN: We analyzed all conference invitations received by the email of one academic plastic surgeon in a 4-month period. These conferences were organized into 3 groups based on affiliation with known professional societies. The following information was collected if available: affiliation with a professional society, type of invitation, conference location, conference format (in-person, virtual, or hybrid), conference title, conference fees, conference organizer, associated journals or publishers, abstract journal submission, grammar, headshots, time to abstract review, and acceptance. RESULTS: There were 56 unique conference invitations. These were categorized into 15 affiliated conferences, 28 unaffiliated conferences, and 17 conferences of undetermined affiliation. Unaffiliated conferences were more likely to solicit speaker invitations ( P < 0.001), claim to be "international" ( P = 0.001), send emails with grammatical errors ( P < 0.001), use unprofessional headshots on the conference Web site ( P < 0.001), and have reduced virtual conference fees ( P = 0.0032) as compared with conferences affiliated with known professional societies. When comparing the attendance and presenter fees of in-person venues, there was no significant difference between affiliated and unaffiliated conferences ( P = 0.973, P = 0.604). Affiliated conferences were more likely to take place in the United States ( P = 0.014). CONCLUSIONS AND RELEVANCE: We present a method to quickly assess the legitimacy of an academic meeting by way of a few important questions. Based on our findings, emails soliciting conference speakers, claims of international presence, grammatical errors, unprofessional headshots, and reduced virtual conference fees are all characteristics that should raise red flags.