Intramolecular autoinhibition regulates the selectivity of PRPF40A tandem WW domains for proline-rich motifs.

PRPF40A plays an important role in the regulation of pre-mRNA splicing by mediating protein-protein interactions in the early steps of spliceosome assembly. By binding to proteins at the 5´ and 3´ splice sites, PRPF40A promotes spliceosome assembly by bridging the recognition of the splices. The PRPF40A WW domains are expected to recognize proline-rich sequences in SF1 and SF3A1 in the early spliceosome complexes E and A, respectively. Here, we combine NMR, SAXS and ITC to determine the structure of the PRPF40A tandem WW domains in solution and characterize the binding specificity and mechanism for proline-rich motifs recognition. Our structure of the PRPF40A WW tandem in complex with a high-affinity SF1 peptide reveals contributions of both WW domains, which also enables tryptophan sandwiching by two proline residues in the ligand. Unexpectedly, a proline-rich motif in the N-terminal region of PRPF40A mediates intramolecular interactions with the WW tandem. Using NMR, ITC, mutational analysis in vitro, and immunoprecipitation experiments in cells, we show that the intramolecular interaction acts as an autoinhibitory filter for proof-reading of high-affinity proline-rich motifs in bona fide PRPF40A binding partners. We propose that similar autoinhibitory mechanisms are present in most WW tandem-containing proteins to enhance binding selectivity and regulation of WW/proline-rich peptide interaction networks.

The Thoracic Surgery Medical Student Association: Understanding the needs of medical students pursuing cardiothoracic surgery in the United States.

OBJECTIVE: Founded in 2020, the Thoracic Surgery Medical Student Association is the first national organization dedicated to supporting medical students interested in pursuing cardiothoracic surgery. Our inaugural survey aimed to describe their basic characteristics and needs. METHODS: An Institutional Review Board-approved, nonincentivized, anonymous electronic survey was distributed to any medical students enrolled in Liaison Committee on Medical Education-accredited medical schools through social media such as Twitter, national organizations (Association of Women Surgeons, Thoracic Surgery Resident Association), and medical school cardiothoracic surgery interest groups. Their basic characteristics, attitudes, and preferences regarding cardiothoracic surgery were recorded. RESULTS: Of the 167 students from 117 unique schools who completed the survey, 53% identified as White and 57% identified as female. Stages of training were well distributed: 16% first-year medical students, 33% second-year medical students, 16% third-year medical students, 21% fourth-year medical students, and 14% dual degree/research students. Most participants (57%) did not have (32%) or were not aware of having (25%) a thoracic surgery training program at their home institution. The majority (72%) of students reported not having a cardiothoracic surgery interest group at their home institution. The most desired areas of cardiothoracic were networking (31%) and mentorship (28%). CONCLUSIONS: There is a significant need to directly engage medical students who are interested in cardiothoracic surgery considering limited exposure at home institutions through a lack of cardiothoracic surgery interest groups and cardiothoracic residency programs. The Thoracic Surgery Medical Student Association is poised to address these areas with directed networking by connecting cardiothoracic surgery faculty and residents from other institutions with medical students interested in pursuing cardiothoracic surgery.

Considerations for a Holistic Model in Evaluating Medical Students for Cardiothoracic Surgical Residency.

Program directors are tasked with selecting whom they think will be the best fit for residency and the next leaders of the field. While numerical metrics have played a vital role in this process, recent changes to student evaluation are reducing the availability of these metrics. This poses unique challenges for both applicants and program directors. Here we discuss how this will likely shift the focus on other parts of the application and the consequences (good and bad) of doing so.

Beyond cardiomyocytes: Cellular diversity in the heart's response to exercise.

Cardiomyocytes comprise ∼70% to 85% of the total volume of the adult mammalian heart but only about 25% to 35% of its total number of cells. Advances in single cell and single nuclei RNA sequencing have greatly facilitated investigation into and increased appreciation of the potential functions of non-cardiomyocytes in the heart. While much of this work has focused on the relationship between non-cardiomyocytes, disease, and the heart's response to pathological stress, it will also be important to understand the roles that these cells play in the healthy heart, cardiac homeostasis, and the response to physiological stress such as exercise. The present review summarizes recent research highlighting dynamic changes in non-cardiomyocytes in response to the physiological stress of exercise. Of particular interest are changes in fibrotic pathways, the cardiac vasculature, and immune or inflammatory cells. In many instances, limited data are available about how specific lineages change in response to exercise or whether the changes observed are functionally important, underscoring the need for further research.

Time since primary transplant and poor functional status predict survival after redo lung transplant.

Background: In previous studies, lower functional status measured by Karnofsky Performance Status (KPS) correlated with worse survival after redo lung transplant. We hypothesize that combining reduced functional status and time from primary lung transplant will correlate with the etiology of lung allograft failure after primary lung transplant and more accurately predict survival after redo lung transplant. Methods: This retrospective study was approved by University of Minnesota Institutional Review Board. From the Scientific Registry of Transplant Recipients (SRTR) database, 739 patients underwent redo lung transplant (01/01/2005-8/30/2019). Pre-lung transplant characteristics, KPS, time between primary and redo lung transplant, outcomes, overall survival were evaluated. Paired comparisons were used to compare pre-transplant variables. A Cox regression model was fit to examine re-transplant survival. Due to non-proportional hazards, time between transplants was split into <1-year vs. 1+ years and analyzed with time-dependent coefficients, with follow-up time considered in three segments (0-6, 6-24, 24+ months). Results: After KPS grouping (10-40%, 50-70%, 80-100%), KPS 10-40% were less likely to be discharged after primary transplant and more likely required mechanical ventilation or extracorporeal membrane oxygenation (ECMO) bridging (P<0.001). Redo lung transplant survival was worse in the KPS 10-40% group who more likely underwent lung transplant <1 year after primary lung transplant. Mortality was significantly higher for patients who underwent redo lung transplant within one year of primary transplant when KPS was 10-40% (P<0.001). These patients were more likely to require redo lung transplant due to primary graft failure or acute cellular rejection. Conclusions: Functional status and time from primary lung transplant are strong predictors of outcome after redo lung transplant. We categorized redo lung transplant recipients in two distinct groups. One group has early allograft failure and poor functional status with a very poor prognosis after redo lung transplant. The other group has chronic allograft failure and overall better functional status with relatively better survival after redo lung transplant. Salvage redo lung transplant for primary allograft failure or acute rejection is associated with low one year survival.

Exercise-induced CITED4 expression is necessary for regional remodeling of cardiac microstructural tissue helicity.

Both exercise-induced molecular mechanisms and physiological cardiac remodeling have been previously studied on a whole heart level. However, the regional microstructural tissue effects of these molecular mechanisms in the heart have yet to be spatially linked and further elucidated. We show in exercised mice that the expression of CITED4, a transcriptional co-regulator necessary for cardioprotection, is regionally heterogenous in the heart with preferential significant increases in the lateral wall compared with sedentary mice. Concordantly in this same region, the heart's local microstructural tissue helicity is also selectively increased in exercised mice. Quantification of CITED4 expression and microstructural tissue helicity reveals a significant correlation across both sedentary and exercise mouse cohorts. Furthermore, genetic deletion of CITED4 in the heart prohibits regional exercise-induced microstructural helicity remodeling. Taken together, CITED4 expression is necessary for exercise-induced regional remodeling of the heart's microstructural helicity revealing how a key molecular regulator of cardiac remodeling manifests into downstream local tissue-level changes.

Plasma Proteomics of COVID-19-Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics.

To gain insights into the mechanisms driving cardiovascular complications in COVID-19, we performed a case-control plasma proteomics study in COVID-19 patients. Our results identify the senescence-associated secretory phenotype, a marker of biological aging, as the dominant process associated with disease severity and cardiac involvement. FSTL3, an indicator of senescence-promoting Activin/TGFß signaling, and ADAMTS13, the von Willebrand Factor-cleaving protease whose loss-of-function causes microvascular thrombosis, were among the proteins most strongly associated with myocardial stress and injury. Findings were validated in a larger COVID-19 patient cohort and the hamster COVID-19 model, providing new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.

Modified Barbero-Marcial repair for type I truncus arteriosus in a 2.7-kg neonate.

Truncus arteriosus is a rare cardiac anomaly, accounting for less than 4% of all congenital lesions. It is the result of failed aorticopulmonary septation during the fifth week of gestation leading to a single arterial trunk overriding the interventricular septum, a single semilunar valve, and typically a large conotruncal ventricular septal defect. Several classifications exist, and it typically requires surgical repair in the neonatal period. We present a 5-day old female neonate who was diagnosed postnatally with type I truncus arteriosus in which the pulmonary arteries arose from a discrete pulmonary trunk that originated from the posterolateral aspect of the common arterial trunk. A successful repair was undertaken using a variant of the Barbero-Marcial technique.

lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth.

BACKGROUND: The heart grows in response to pathological and physiological stimuli. The former often precedes cardiomyocyte loss and heart failure; the latter paradoxically protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Although long noncoding RNAs (lncRNAs) are important in cardiac development and disease, less is known about their roles in physiological hypertrophy or cardiomyogenesis. METHODS: RNA sequencing was applied to hearts from mice after 8 weeks of voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction for 2 or 8 weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus vectors and inhibited with antisense locked nucleic acid-GapmeRs to examine its function. Downstream effectors were identified through promoter analyses and binding assays. The functional roles of a novel downstream effector, dachsous cadherin-related 2 (DCHS2), were examined through transgenic overexpression in zebrafish and cardiac-specific deletion in Cas9-knockin mice. RESULTS: We identified exercise-regulated cardiac lncRNAs, called lncExACTs. lncExACT1 was evolutionarily conserved and decreased in exercised hearts but increased in human and experimental heart failure. Cardiac lncExACT1 overexpression caused pathological hypertrophy and heart failure; lncExACT1 inhibition induced physiological hypertrophy and cardiomyogenesis, protecting against cardiac fibrosis and dysfunction. lncExACT1 functioned by regulating microRNA-222, calcineurin signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCHS2 overexpression in zebrafish induced pathological hypertrophy and impaired cardiac regeneration, promoting scarring after injury. In contrast, murine DCHS2 deletion induced physiological hypertrophy and promoted cardiomyogenesis. CONCLUSIONS: These studies identify lncExACT1-DCHS2 as a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1-DCHS2 acts as a master switch toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the beneficial effects of exercise.

Non-Governmental Organizations Delivering Global Cardiac Surgical Care: A Quantitative Impact Assessment.

In low- and middle-income countries (LMICs), 93% of the population lacks safe, timely, and affordable access to cardiac surgical care when needed. As countries slowly build or expand local, independent cardiac centers, non-governmental organizations (NGOs) partially bridge the gap in cardiac surgical care delivery in LMICs. However, little is known about the current scope of cardiac NGOs. Here, we perform an analysis of active NGOs involved with the delivery of cardiac surgical services in LMICs or for patients from LMICs. Cardiac surgery NGOs were identified from medical literature, established NGO databases, and Google Scholar searches. The search was performed between December 2019 and May 2020. NGOs whose websites were not updated or described missions or projects taking place no later than 2015 were considered inactive. Eighty-six NGOs are actively providing cardiac surgery services in LMICs or treating patients from LMICs. Five NGOs performed adult cardiac surgery only, 56 performed pediatric cardiac surgery only, and 25 performed both adult and pediatric cardiac surgery. NGOs originated from 23 different countries and were operational in a total of 111 countries, 96 of them being LMICs. Fifty-three NGOs reported data on annual surgical volume, of which half performed less than 50 operations per year. NGOs effectively address the burden of cardiac surgical disease in LMICs and contribute to local capacity-building. Increased, more detailed, and standardized reporting of the impact and outcomes of NGOs is necessary to better understand annual cardiac surgical volume and to support local centers working towards independent services.

Surgical Aortic Valve Replacement Outcomes in Non-Transcatheter Aortic Valve Replacement Centers: Implications for Tier-Based Systems of Care.

BACKGROUND: With wide expansion of transcatheter aortic valve replacement (TAVR) and dissemination of multidisciplinary-based approaches to care, societies are discussing the implementation of a tier system to valve centers. This study explores the impact of tier-based systems of care on surgical aortic valve replacement (SAVR) outcomes at institutions that perform SAVR only. METHODS: Medicare beneficiaries undergoing SAVR procedures from 2012 to 2015 were included. The SAVR hospitals were stratified into either tier A, valve centers with a TAVR program; or tier B, valve centers without a TAVR program. Adjusted survival, assessed by multivariable Cox regression, controlled for program type and patient risk profile. Time-dependent analysis accounted for hospitals that initiated a TAVR program during the study period. RESULTS: Overall, there were 562 tier A and 485 tier B SAVR hospitals. Tier A hospitals had significantly higher comorbidity burden compared with tier B hospitals (all P < .05) but had significantly lower rates of 30-day mortality (3.2% vs 4.1%) and 1-year mortality (8.1% vs 9.4%; both P < .05). After risk stratification, tier B hospitals had significantly worse 30-day mortality compared with tier A hospitals for all patient risk-profiles, except for the low-risk patients (P < .01). These findings persisted in the time-dependent analysis. Adjusted midterm survival was higher in tier A vs tier B hospitals. CONCLUSIONS: Low-risk patients can safely undergo SAVR in both tier level hospitals without compromising outcomes. Establishment of quality of care measures, especially in the SAVR-only hospitals, remains paramount and should be closely integrated when designing tier-based systems for aortic valve replacement care.

Coproduction in medical education during the COVID-19 pandemic: critical components of successful curricular reform.

The current coronavirus disease 2019 pandemic has greatly affected medical education in unanticipated ways. By introducing the concept of educational coproduction at our institution, we have maintained a flexible and productive curricular environment for all students. The notion of coproduction acknowledges that education is a service that requires recognition of the expertise that both the teacher and the learner bring to the table, in the context of their community and society writ large. Using the coproduction framework allowed for increased communication and improved partnerships among students, educators, clinicians and our community as well as adaptations to a rapidly changing educational environment. Embracing the idea of coproduction is a valuable concept for institutions to consider during this time and in the future post-pandemic period.

Plasma Proteomics of COVID-19 Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics.

Cardiovascular complications are common in COVID-19 and strongly associated with disease severity and mortality. However, the mechanisms driving cardiac injury and failure in COVID-19 are largely unknown. We performed plasma proteomics on 80 COVID-19 patients and controls, grouped according to disease severity and cardiac involvement. Findings were validated in 305 independent COVID-19 patients and investigated in an animal model. Here we show that senescence-associated secretory proteins, markers of biological aging, strongly associate with disease severity and cardiac involvement even in age-matched cohorts. FSTL3, an indicator of Activin/TGFß signaling, was the most significantly upregulated protein associated with the heart failure biomarker, NTproBNP (ß = 0.4;p adj =4.6x10 - 7 ), while ADAMTS13, a vWF-cleaving protease whose loss-of-function causes microvascular thrombosis, was the most downregulated protein associated with myocardial injury (ß=-0.4;p adj =8x10 - 7 ). Mendelian randomization supported a causal role for ADAMTS13 in myocardial injury. These data provide important new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.

Resection of a large left atrial myxoma combined with mitral valve repair via a vertical right axillary thoracotomy in a pediatric patient.

Cardiac myxomas are extremely rare in the pediatric population; however, if they do develop, they occur most often in the left atrium. We present a 16-year-old male who had a murmur discovered during a routine sport examination. A transthoracic echocardiogram showed a large left atrial tumor that caused severe inflow obstruction to the left ventricle and at least moderate mitral valve regurgitation. Through a minimally invasive, muscle-sparing vertical right axillary thoracotomy, he underwent complete resection of the mass, combined with posterior mitral valve annuloplasty. A histopathological examination confirmed a cardiac myxoma.