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The rapid emergence and exploding usage of online social networking forums, which are frequented by millions, present clinicians with new ethical and professional challenges. Particularly among a younger generation of physicians and patients, the use of online social networking forums has become widespread. In this article, we discuss ethical challenges facing the patient-doctor relationship as a result of the growing use of online social networking forums. We draw upon one heavily used and highly trafficked forum, Facebook, to illustrate the elements of these online environments and the ethical challenges peculiar to their novel form of exchange. Finally, we present guidelines for clinicians to negotiate responsibly and professionally their possible uses of these social forums. [ABSTRACT FROM AUTHOR]

Background: Achievement of guideline-recommended levels of physical activity (≥150 minutes of moderate-to-vigorous physical activity per week) is associated with lower risk of adverse cardiovascular events and represents an important public health priority. Although physical activity commonly follows a "weekend warrior" pattern, in which most moderate-to-vigorous physical activity is concentrated in 1 or 2 days rather than spread more evenly across the week (regular), the effects of physical activity pattern across a range of incident diseases, including cardiometabolic conditions, are unknown., Methods: We tested associations between physical activity pattern and incidence of 678 conditions in 89 573 participants (62±8 years of age; 56% women) of the UK Biobank prospective cohort study who wore an accelerometer for 1 week between June 2013 and December 2015. Models were adjusted for multiple baseline clinical factors, and P value thresholds were corrected for multiplicity., Results: When compared to inactive (<150 minutes moderate-to-vigorous physical activity/week), both weekend warrior (267 total associations; 264 [99%] with lower disease risk; hazard ratio [HR] range, 0.35-0.89) and regular activity (209 associations; 205 [98%] with lower disease risk; HR range, 0.41-0.88) were broadly associated with lower risk of incident disease. The strongest associations were observed for cardiometabolic conditions such as incident hypertension (weekend warrior: HR, 0.77 [95% CI, 0.73-0.80]; P =1.2×10 -27 ; regular: HR, 0.72 [95% CI, 0.68-0.77]; P =4.5×10 -28 ), diabetes (weekend warrior: HR, 0.57 [95% CI, 0.51-0.62]; P =3.9×10 -32 ; regular: HR, 0.54 [95% CI, 0.48-0.60]; P =8.7×10 -26 ), obesity (weekend warrior: HR, 0.55 [95% CI, 0.50-0.60]; P =2.4×10 -43 , regular: HR, 0.44 [95% CI, 0.40-0.50]; P =9.6×10 -47 ), and sleep apnea (weekend warrior: HR, 0.57 [95% CI, 0.48-0.69]; P =1.6×10 -9 ; regular: HR, 0.49 [95% CI, 0.39-0.62]; P =7.4×10 -10 ). When weekend warrior and regular activity were compared directly, there were no conditions for which effects differed significantly. Observations were similar when activity was thresholded at the sample median (≥230.4 minutes of moderate-to-vigorous physical activity/week)., Conclusions: Achievement of measured physical activity volumes consistent with guideline recommendations is associated with lower risk for >200 diseases, with prominent effects on cardiometabolic conditions. Associations appear similar whether physical activity follows a weekend warrior pattern or is spread more evenly throughout the week., Competing Interests: P.T.E. receives sponsored research support from Bayer AG, Bristol Myers Squibb, Pfizer, and Novo Nordisk; he has also served on advisory boards or consulted for Bayer AG. S.A.L. is an employee of Novartis as of July 2022. S.A.L. received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. The other authors report no conflicts.

Importance: Racial disparities in cardiovascular health, including sudden cardiac death (SCD), exist among both the general and athlete populations. Among competitive athletes, disparities in health outcomes potentially influenced by social determinants of health (SDOH) and structural racism remain inadequately understood. This narrative review centers on race in sports cardiology, addressing racial disparities in SCD risk, false-positive cardiac screening rates among athletes, and the prevalence of left ventricular hypertrophy, and encourages a reexamination of race-based practices in sports cardiology, such as the interpretation of screening 12-lead electrocardiogram findings., Observations: Drawing from an array of sources, including epidemiological data and broader medical literature, this narrative review discusses racial disparities in sports cardiology and calls for a paradigm shift in approach that encompasses 3 key principles: race-conscious awareness, clinical inclusivity, and research-driven refinement of clinical practice. These proposed principles call for a shift away from race-based assumptions towards individualized, health-focused care in sports cardiology. This shift would include fostering awareness of sociopolitical constructs, diversifying the medical team workforce, and conducting diverse, evidence-based research to better understand disparities and address inequities in sports cardiology care., Conclusions and Relevance: In sports cardiology, inadequate consideration of the impact of structural racism and SDOH on racial disparities in health outcomes among athletes has resulted in potential biases in current normative standards and in the clinical approach to the cardiovascular care of athletes. An evidence-based approach to successfully address disparities requires pivoting from outdated race-based practices to a race-conscious framework to better understand and improve health care outcomes for diverse athletic populations.

Cardiac aging is an intricate and multifaceted process with considerable impact on public health, especially given the global demographic shift towards aged populations. This review discusses structural, cellular and functional changes associated with cardiac aging and heart failure with preserved ejection fraction (HFpEF). Key molecular mediators are considered within the framework of the established hallmarks of aging, with particular attention to promising therapeutic candidates. We further delineate the differential impacts of aging on cardiac structure and function in men and women, addressing hormonal and chromosomal influences. The protective and mitigating effects of exercise in cardiac aging and HFpEF in particular are discussed, as an inspiration for the identification of pathways that mitigate biological aging. We also emphasize how much remains to be learned and the importance of these efforts in enhancing the cardiac health of aging populations worldwide., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The mechanisms underlying the psychological and cardiovascular disease (CVD) benefits of physical activity (PA) are not fully understood., Objectives: This study tested whether PA: 1) attenuates stress-related neural activity, which is known to potentiate CVD and for its role in anxiety/depression; 2) decreases CVD in part through this neural effect; and 3) has a greater impact on CVD risk among individuals with depression., Methods: Participants from the Mass General Brigham Biobank who completed a PA survey were studied. A subset underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomographic imaging. Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygA C ). CVD events were ascertained from electronic health records., Results: A total of 50,359 adults were included (median age 60 years [Q1-Q3: 45-70 years]; 40.1% male). Greater PA was associated with both lower AmygA C (standardized β: -0.245; 95% CI: -0.444 to -0.046; P = 0.016) and CVD events (HR: 0.802; 95% CI: 0.719-0.896; P < 0.001) in multivariable models. AmygA C reductions partially mediated PA's CVD benefit (OR: 0.96; 95% CI: 0.92-0.99; P < 0.05). Moreover, PA's benefit on incident CVD events was greater among those with (vs without) preexisting depression (HR: 0.860; 95% CI: 0.810-0.915; vs HR: 0.929; 95% CI: 0.910-0.949; P interaction = 0.011). Additionally, PA above guideline recommendations further reduced CVD events, but only among those with preexisting depression (P interaction = 0.023)., Conclusions: PA appears to reduce CVD risk in part by acting through the brain's stress-related activity; this may explain the novel observation that PA reduces CVD risk to a greater extent among individuals with depression., Competing Interests: Funding Support and Author Disclosures This study is in part funded by National Institutes of Health (NIH) grants R56AR077187-01 and P01HL131478-05. This study was in part supported by NIH grants 1R01AR077187 (Dr Tawakol), P01HL131478 (Drs Tawakol and Fayad), K23HL151909 (Dr Osborne). Dr Osborne has received consulting fees from WCG Intrinsic Imaging, LLC, for unrelated work. Dr Choi has received support in part by funding from the National Institute of Mental Health (K08MH127413) and a NARSAD Brain and Behavior Foundation Young Investigator Award. Dr Smoller has received support for work outside the submitted research; is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity); has received an honorarium for an internal seminar at Tempus Labs and Biogen, Inc; and is PI of a study sponsored by 23andMe. Dr Tawakol has received grants from the National Institutes of Health, International Atomic Energy Agency, Osler/Harvard, and Lung Biotechnologies for work outside the submitted research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: To leverage deep learning on the resting 12-lead electrocardiogram (ECG) to estimate peak oxygen consumption (V˙O2peak) without cardiopulmonary exercise testing (CPET)., Methods and Results: V ˙ O 2 peak estimation models were developed in 1891 individuals undergoing CPET at Massachusetts General Hospital (age 45 ± 19 years, 38% female) and validated in a separate test set (MGH Test, n = 448) and external sample (BWH Test, n = 1076). Three penalized linear models were compared: (i) age, sex, and body mass index ('Basic'), (ii) Basic plus standard ECG measurements ('Basic + ECG Parameters'), and (iii) basic plus 320 deep learning-derived ECG variables instead of ECG measurements ('Deep ECG-V˙O2'). Associations between estimated V˙O2peak and incident disease were assessed using proportional hazards models within 84 718 primary care patients without CPET. Inference ECGs preceded CPET by 7 days (median, interquartile range 27-0 days). Among models, Deep ECG-V˙O2 was most accurate in MGH Test [r = 0.845, 95% confidence interval (CI) 0.817-0.870; mean absolute error (MAE) 5.84, 95% CI 5.39-6.29] and BWH Test (r = 0.552, 95% CI 0.509-0.592, MAE 6.49, 95% CI 6.21-6.67). Deep ECG-V˙O2 also outperformed the Wasserman, Jones, and FRIEND reference equations (P < 0.01 for comparisons of correlation). Performance was higher in BWH Test when individuals with heart failure (HF) were excluded (r = 0.628, 95% CI 0.567-0.682; MAE 5.97, 95% CI 5.57-6.37). Deep ECG-V˙O2 estimated V˙O2peak <14 mL/kg/min was associated with increased risks of incident atrial fibrillation [hazard ratio 1.36 (95% CI 1.21-1.54)], myocardial infarction [1.21 (1.02-1.45)], HF [1.67 (1.49-1.88)], and death [1.84 (1.68-2.03)]., Conclusion: Deep learning-enabled analysis of the resting 12-lead ECG can estimate exercise capacity (V˙O2peak) at scale to enable efficient cardiovascular risk stratification., Competing Interests: Conflict of interest: B.M.W. has consulted for Change Healthcare. P.D.A. and P.B. are supported by grants from Bayer AG and IBM applying machine learning in cardiovascular disease. P.B. serves as a consultant for Novartis and Prometheus Biosciences. P.T.E. receives sponsored research support from Bayer AG and IBM Research; he has also served on advisory boards or consulted for Bayer AG, MyoKardia, and Novartis. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers Squibb/Pfizer, Bayer AG, and Blackstone Life Sciences. S.A.L. is now an employee of Novartis Institute for Biomedical Research. The remaining authors have no disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Conflict of interest: None declared.

Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value < 0.1). Prostaglandin (15R-PGF2α, 11ß-dhk-PGF2α) and linoleic acid derivatives (12,13 EpOME) are associated with greater odds of HFpEF, while epoxides (8(9)-EpETE), docosanoids (13,14-DiHDPA), and oxylipins (12-OPDA) are associated with lower odds of HFpEF. Among 70 metabolites, 18 are associated with future development of heart failure in the community. Pro- and anti-inflammatory eicosanoid and related metabolites may contribute to the pathogenesis of HFpEF and serve as potential targets for intervention., (© 2023. The Author(s).)

Competing Interests: Disclosures None.

The use of consumer wearable devices (CWDs) to track health and fitness has rapidly expanded over recent years because of advances in technology. The general population now has the capability to continuously track vital signs, exercise output, and advanced health metrics. Although understanding of basic health metrics may be intuitive (eg, peak heart rate), more complex metrics are derived from proprietary algorithms, differ among device manufacturers, and may not historically be common in clinical practice (eg, peak V˙O 2 , exercise recovery scores). With the massive expansion of data collected at an individual patient level, careful interpretation is imperative. In this review, we critically analyze common health metrics provided by CWDs, describe common pitfalls in CWD interpretation, provide recommendations for the interpretation of abnormal results, present the utility of CWDs in exercise prescription, examine health disparities and inequities in CWD use and development, and present future directions for research and development., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Guidelines recommend 150 minutes or more of moderate to vigorous physical activity (MVPA) per week for overall health benefit, but the relative effects of concentrated vs more evenly distributed activity are unclear., Objective: To examine associations between an accelerometer-derived "weekend warrior" pattern (ie, most MVPA achieved over 1-2 days) vs MVPA spread more evenly with risk of incident cardiovascular events., Design, Setting, and Participants: Retrospective analysis of UK Biobank cohort study participants providing a full week of accelerometer-based physical activity data between June 8, 2013, and December 30, 2015., Exposures: Three MVPA patterns were compared: active weekend warrior (active WW, ≥150 minutes with ≥50% of total MVPA achieved in 1-2 days), active regular (≥150 minutes and not meeting active WW status), and inactive (<150 minutes). The same patterns were assessed using the sample median threshold of 230.4 minutes or more of MVPA per week., Main Outcomes and Measures: Associations between activity pattern and incident atrial fibrillation, myocardial infarction, heart failure, and stroke were assessed using Cox proportional hazards regression, adjusted for age, sex, racial and ethnic background, tobacco use, alcohol intake, Townsend Deprivation Index, employment status, self-reported health, and diet quality., Results: A total of 89 573 individuals (mean [SD] age, 62 [7.8] years; 56% women) who underwent accelerometry were included. When stratified at the threshold of 150 minutes or more of MVPA per week, a total of 37 872 were in the active WW group (42.2%), 21 473 were in the active regular group (24.0%), and 30 228 were in the inactive group (33.7%). In multivariable-adjusted models, both activity patterns were associated with similarly lower risks of incident atrial fibrillation (active WW: hazard ratio [HR], 0.78 [95% CI, 0.74-0.83]; active regular: 0.81 [95% CI, 0.74-0.88; inactive: HR, 1.00 [95% CI, 0.94-1.07]), myocardial infarction (active WW: 0.73 [95% CI, 0.67-0.80]; active regular: 0.65 [95% CI, 0.57-0.74]; and inactive: 1.00 [95% CI, 0.91-1.10]), heart failure (active WW: 0.62 [95% CI, 0.56-0.68]; active regular: 0.64 [95% CI, 0.56-0.73]; and inactive: 1.00 [95% CI, 0.92-1.09]), and stroke (active WW: 0.79 [95% CI, 0.71-0.88]; active regular: 0.83 [95% CI, 0.72-0.97]; and inactive: 1.00 [95% CI, 0.90-1.11]). Findings were consistent at the median threshold of 230.4 minutes or more of MVPA per week, although associations with stroke were no longer significant (active WW: 0.89 [95% CI, 0.79-1.02]; active regular: 0.87 [95% CI, 0.74-1.02]; and inactive: 1.00 [95% CI, 0.90-1.11])., Conclusions and Relevance: Physical activity concentrated within 1 to 2 days was associated with similarly lower risk of cardiovascular outcomes to more evenly distributed activity.

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., Competing Interests: Competing interests The authors declare that they have no competing interests., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Competing Interests: Conflict of interest: None declared.

Objective: To examine the relationships between age, healthspan and chronic illness among former professional American-style football (ASF) players., Methods: We compared age-specific race-standardised and body mass index-standardised prevalence ratios of arthritis, dementia/Alzheimer's disease, hypertension and diabetes among early adult and middle-aged (range 25-59 years) male former professional ASF players (n=2864) with a comparator cohort from the National Health and Nutrition Examination Survey and National Health Interview Survey, two representative samples of the US general population. Age was stratified into 25-29, 30-39, 40-49 and 50-59 years., Results: Arthritis and dementia/Alzheimer's disease were more prevalent among ASF players across all study age ranges (all p<0.001). In contrast, hypertension and diabetes were more prevalent among ASF players in the youngest age stratum only (p<0.001 and p<0.01, respectively). ASF players were less likely to demonstrate intact healthspan (ie, absence of chronic disease) than the general population across all age ranges., Conclusion: These data suggest the emergence of a maladaptive early ageing phenotype among former professional ASF players characterised by premature burden of chronic disease and reduced healthspan. Additional study is needed to investigate these findings and their impact on morbidity and mortality in former ASF players and other athlete groups., Competing Interests: Competing interests: The Football Players Health Study is supported by the NFL Players Association. The NFL Players Association did not contribute to the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. This work received support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR002541) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. The authors wish to acknowledge the study participants, advisors and staff of the Football Players Health Study for their time and effort., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Acute and chronic animal models of exercise are commonly used in research. Acute exercise testing is used, often in combination with genetic, pharmacological, or other manipulations, to study the impact of these manipulations on the cardiovascular response to exercise and to detect impairments or improvements in cardiovascular function that may not be evident at rest. Chronic exercise conditioning models are used to study the cardiac phenotypic response to regular exercise training and as a platform for discovery of novel pathways mediating cardiovascular benefits conferred by exercise conditioning that could be exploited therapeutically. The cardiovascular benefits of exercise are well established, and, frequently, molecular manipulations that mimic the pathway changes induced by exercise recapitulate at least some of its benefits. This review discusses approaches for assessing cardiovascular function during an acute exercise challenge in rodents, as well as practical and conceptual considerations in the use of common rodent exercise conditioning models. The case for studying feeding in the Burmese python as a model for exercise-like physiological adaptation is also explored.

Objectives: Persistent or late-onset cardiopulmonary symptoms following COVID-19 may occur in athletes despite a benign initial course. We examined the yield of cardiac evaluation, including cardiopulmonary exercise testing (CPET), in athletes with cardiopulmonary symptoms after COVID-19, compared CPETs in these athletes and those without COVID-19 and evaluated longitudinal changes in CPET with improvement in symptoms., Methods: This prospective cohort study evaluated young (18-35 years old) athletes referred for cardiopulmonary symptoms that were present>28 days from COVID-19 diagnosis. CPET findings in post-COVID athletes were compared with a matched reference group of healthy athletes without COVID-19. Post-COVID athletes underwent repeat CPET between 3 and 6 months after initial evaluation., Results: Twenty-one consecutive post-COVID athletes with cardiopulmonary symptoms (21.9±3.9 years old, 43% female) were evaluated 3.0±2.1 months after diagnosis. No athlete had active inflammatory heart disease. CPET reproduced presenting symptoms in 86%. Compared with reference athletes (n=42), there was similar peak VO 2 but a higher prevalence of abnormal spirometry (42%) and low breathing reserve (42%). Thirteen athletes (62%) completed longitudinal follow-up (4.8±1.9 months). The majority (69%) had reduction in cardiopulmonary symptoms, accompanied by improvement in peak VO 2 and oxygen pulse, and reduction in resting and peak heart rate (all p<0.05)., Conclusion: Despite a high burden of cardiopulmonary symptoms after COVID-19, no athlete had active inflammatory heart disease. CPET was clinically useful to reproduce symptoms with either normal testing or identification of abnormal spirometry as a potential therapeutic target. Improvement in post-COVID symptoms was accompanied by improvements in CPET parameters., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Oxygen uptake (V̇o 2 ) at exercise onset is determined in part by acceleration of pulmonary blood flow ([Formula: see text]). Impairments in the [Formula: see text] response can decrease exercise tolerance. Prior research has shown that voluntary respiratory maneuvers can augment venous return, but the corollary impacts on cardiac function, [Formula: see text] and early-exercise V̇o 2 remain uncertain. We examined 1 ) the cardiovascular effects of three distinct respiratory maneuvers (abdominal, AB; rib cage, RC; and deep breathing, DB) under resting conditions in healthy subjects ( Protocol 1 , n = 13), and 2 ) the impact of pre-exercise DB on pulmonary O 2 transfer during initiation of moderate-intensity exercise ( Protocol 2 , n = 8). In Protocol 1 , echocardiographic analysis showed increased right ventricular (RV) cardiac output and left ventricular (LV) cardiac output (RVCO and LVCO, respectively), following AB (by +23 ± 13 and +18 ± 15%, respectively, P < 0.05), RC (+23 ± 16; +14 ± 15%, P < 0.05), and DB (+27 ± 21; +23 ± 14%, P < 0.05). In Protocol 2 , DB performed for 12 breaths produced a pre-exercise increase in V̇o 2 (+801 ± 254 mL·min -1 over ∼6 s), presumably from increased [Formula: see text], followed by a reduction in pulmonary O 2 transfer during early phase exercise (first 20 s) compared with the control condition (149 ± 51 vs. 233 ± 65 mL, P < 0.05). We conclude that 1 ) respiratory maneuvers enhance RVCO and LVCO in healthy subjects under resting conditions, 2 ) AB, RC, and DB have similar effects on RVCO and LVCO, and 3 ) DB can increase [Formula: see text] before exercise onset. These findings suggest that pre-exercise respiratory maneuvers may represent a promising strategy to prime V̇o 2 kinetics and thereby to potentially improve exercise tolerance in patients with impaired cardiac function. NEW & NOTEWORTHY We demonstrate that different breathing maneuvers can augment both right and left-sided cardiac output in healthy subjects. These maneuvers, when performed immediately before exercise, result in a pre-exercise "cardiodynamic" increase in oxygen uptake (V̇o 2 ) associated with a subsequent reduction in the "cardiodynamic" V̇o 2 normally seen during early exercise. We conclude that pre-exercise breathing maneuvers are a plausible tool worthy of additional study to prime V̇o 2 kinetics and improve exercise tolerance in patients with cardiovascular disease.

Introduction: Cardiorespiratory fitness (CRF), as one of the most potent prognostic factors in medicine, is followed longitudinally to guide clinical management. Coronavirus disease 2019 (COVID-19) pandemic-related changes in lifestyle stand to influence CRF., Objective: To assess the influence of the pandemic on perceived CRF in athlete patients and evaluate how perceived CRF change was related to demographics, pre-pandemic measured CRF, and current physical activity (PA)., Design: Prospective cohort study, utilizing electronic survey., Setting: Tertiary care sports cardiology clinical practice., Participants: Adult athlete patients without COVID-19 with pre-pandemic measured CRF using cardiopulmonary exercise testing., Interventions: Not applicable., Main Outcome Measures: Perceived change in CRF since pandemic onset; association between perceived CRF change and demographics, PA, health status, and pre-pandemic measured CRF assessed via analysis of variance (ANOVA)., Results: Among 62 participants (male: 71%, 50.1 ± 12.1 years old), 40% (25/62) reported no change and 32% (20/62) reported an increase in perceived CRF since pandemic onset. Among the 27% (17/62) who reported a decrease in perceived CRF, in most (12/17), this was characterized as only mild. Demographics and pre-pandemic measured CRF did not differ across groups of perceived CRF change. Participants with a moderate or greater decrease in perceived CRF regarded their overall health (via Euro Quality of Life Visual Analogue Scale) as worse than other groups (ANOVA, p = .001). Although total PA was similar across groups, those who had improvement in perceived CRF reported higher levels of moderate intensity PA (ANOVA, p = .008)., Conclusions: The majority of participants perceived that they had maintained or improved CRF over the pandemic. Findings from this study suggest that a reduction in perceived CRF from pre-pandemic values in athletic patients in clinical practice may not result from population-wide pandemic changes in lifestyle. Worse health status and lower levels of moderate intensity PA were associated with perceived reduction in CRF over the pandemic in athlete patients., (© 2022 American Academy of Physical Medicine and Rehabilitation.)

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/TGFβ 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., Competing Interests: This work was supported by the National Institutes of Health (R01AG061034 and R35HL15531 [to Dr Rosenzweig]; R01HL092577, R01HL128914, and K24HL105780 [to Dr Ellinor]; R01HL134893, R01HL140224, K24HL153669 [to Dr Ho]; T32HL094301 [to Dr Weber]; K08HL140200 [to Dr Rhee]; and K76AG064328 [to Dr Roh]), the Fondation Leducq (14CVD01 [to Dr Ellinor]), the American Heart Association (18SFRN34110082 [to Dr Ellinor]), a Sarnoff Cardiovascular Research Foundation Fellowship award (to Dr Trager), the Fred and Ines Yeatts Fund for Innovative Research (to Dr Roh), the Hassenfeld Scholars Award (to Dr Roh), Fast Grants, Emergent Ventures, Mercatus Center at George Mason University (to Dr Martinot), and a research grant from Bayer AG to the Broad Institute (to Drs Ellinor and Ho). Dr Ellinor is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases; and has served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. Dr Ho has received research grants from Bayer AG and Gilead Sciences; and has received research supplies from EcoNugenics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Aims: Accurate interpretation of cardiopulmonary exercise testing (CPET) relies on age, gender, and exercise modality-specific reference values. To date, clinically applicable CPET reference values derived from a source population of endurance athletes (EAs) have been lacking. The purpose of this study was to generate CPET reference values for use in the clinical assessment of EA., Methods and Results: Prospective data accrued during the clinical care of healthy EA were used to derive CPET reference values and to develop novel equations for V˙O2peak. The performance of these equations was compared to the contemporary standard of care equations and assessed in a discrete EA validation cohort. A total of 272 EA (age = 42 ± 15 years, female = 31%, V˙O2peak = 3.6 ± 0.83 L/min) met inclusion criteria and comprised the derivation cohort. V˙O2peak prediction equations derived from general population cohorts described a modest amount of V˙O2peak variability [R2 = 0.58-0.70, root mean square error (RMSE) = 0.46-0.54 L/min] but were mis-calibrated (calibration-in-the-large = 0.45-1.18 L/min) among EA leading to significant V˙O2peak underestimation. Newly derived, externally validated V˙O2peak prediction equations for EA that included age, sex, and height for both treadmill (R2 = 0.74, RMSE = 0.42 L/min) and cycle ergometer CPET (Cycle: R2 = 0.69, RMSE = 0.42 L/min) demonstrated improved accuracy., Conclusion: Commonly used V˙O2peak prediction equations derived from general population cohorts perform poorly among competitive EA. Newly derived CPET reference values including novel V˙O2peak prediction equations may improve the clinical utility of CPET in this rapidly growing patient population., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Purpose: Although exercise testing guidelines define cutoffs for an exaggerated exercise systolic blood pressure (SBP) response, SBPs above these cutoffs are not uncommon in athletes given their high exercise capacity. Alternately, guidelines also specify a normal SBP response that accounts for metabolic equivalents (METs; mean [SD] of 10 [2] mm Hg per MET or 3.5 mL/kg/min oxygen consumption [V˙o 2 ]). SBP and V˙o 2 increase less during exercise in females than males. It is not clear if sex-based differences in exercise SBP are related to differences in V˙o 2 or if current recommendations for normal increase in SBP per MET produce reasonable estimates using measured METs (ie, V˙o 2 ) in athletes. We therefore examined sex-based differences in exercise SBP indexed to V˙o 2 in athletes with the goal of defining normative values for exercise SBP that account for fitness and sex., Methods: Using prospectively collected data from a single sports cardiology program, normotensive athlete patients were identified who had no relevant cardiopulmonary disease and had undergone cardiopulmonary exercise testing with cycle ergometry or treadmill. The relationship between ΔSBP (peak - rest) and ΔV˙o 2 (peak - rest) was examined in the total cohort and compared between sexes., Findings: A total of 413 athletes (mean [SD] age, 35.5 [14] years; 38% female; mean [SD] peak V˙o 2 , 46.0 [10.2] mL/kg/min, 127% [27%] predicted) met the inclusion criteria. The ΔSBP correlated with unadjusted ΔV˙o 2 (cycle: R 2  = 0.18, treadmill: R 2  = 0.12; P < 0.0001). Female athletes had lower mean (SD) peak SBP (cycle: 161 [15] vs 186 [24] mm Hg; treadmill: 165 [17] vs 180 [20] mm Hg; P < 0.05) than male athletes. Despite lower peak SBP, mean (SD) ΔSBP relative to unadjusted ΔV˙o 2 was higher in female than male athletes (cycle: 25.6 [7.2] vs 21.1 [7.3] mm Hg/L/min; treadmill: 21.6 [7.2] vs 17.0 [6.2] mm Hg/L/min; P < 0.05). When V˙o 2 was adjusted for body size and converted to METs, female and male athletes had similar mean (SD) ΔSBP /ΔMET (cycle: 6.0 [2.1] vs 5.8 [2.0] mm Hg/mL/kg/min; treadmill: 4.7 [1.8] vs 4.8 [1.7] mm Hg/mL/kg/min)., Implications: In this cohort of athletes without known cardiopulmonary disease, observed sex-based differences in peak exercise SBP were in part related to the differences in ΔV˙o 2 between male and female athletes. Despite lower peak SBP, ΔSBP/unadjusted ΔV˙o 2 was paradoxically higher in female athletes. Future work should define whether this finding reflects sex-based differences in the peripheral vascular response to exercise. In this athletic cohort, ΔSBP/ΔMET was similar between sexes and much lower than the ratio that has been proposed by guidelines to define a normal SBP response. Our observed ΔSBP/ΔMET, based on measured rather than estimated METs, provides a clinically useful estimate for normal peak SBP range in athletes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

An increasing number of individuals travel to mountainous environments for work and pleasure. However, oxygen availability declines at altitude, and hypoxic environments place unique stressors on the cardiovascular system. These stressors may be exacerbated by exercise at altitude, because exercise increases oxygen demand in an environment that is already relatively oxygen deplete compared with sea-level conditions. Furthermore, the prevalence of cardiovascular disease, as well as diseases such as hypertension, heart failure, and lung disease, is high among individuals living in the United States. As such, patients who are at risk of or who have established cardiovascular disease may be at an increased risk of adverse events when sojourning to these mountainous locations. However, these risks may be minimized by appropriate pretravel assessments and planning through shared decision-making between patients and their managing clinicians. This American Heart Association scientific statement provides a concise, yet comprehensive overview of the physiologic responses to exercise in hypoxic locations, as well as important considerations for minimizing the risk of adverse cardiovascular events during mountainous excursions.

Background: Postoperative delirium (POD) is an acute altered mental state commonly encountered after cardiac surgery. The pathophysiological mechanisms underlying POD remain unclear. We aimed to identify circulating proteins significantly altered after major cardiac surgery with cardiopulmonary bypass (CPB). We also aimed to enable inferences on associations with POD., Methods: Serum and whole blood samples were collected before CPB ( n = 16 patients; n = 8 with POD) and again from the same patients on postoperative day 1. All patients were clinically evaluated for POD on postoperative days 1-3. An aptamer-based proteomics platform (SOMAscan) was used to quantify serum protein abundance in patients with POD compared with non-POD controls. We also performed a lipopolysaccharide (LPS)-based in vitro functional analysis (TruCulture) on whole blood samples from patients with POD and non-POD controls to approximate surgical stress. Cytokine levels were determined using a Luminex immunoassay., Results: Cardiac surgery with CPB resulted in a significant ( p adj < 0.01) change in 48.8% (637 out of 1,305) of proteins detected by SOMAscan. Gene set enrichment showed that the most impacted biological processes involved myeloid cell activation. Specifically, activation and degranulation of neutrophils were the top five highest-scoring processes. Pathway analyses with the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that metabolic enzymes, particularly those of glycolysis, were elevated in serum concentration after surgery. Several proteins were significantly increased postoperatively in patients diagnosed with POD relative to the non-POD controls, with interleukin-6 (IL-6) showing the greatest fold-change. LPS stimulation of whole blood samples confirmed these findings. Linear regression analysis showed a highly significant correlation between Confusion Assessment Method (CAM) scores and CPB-mediated changes in cGMP-inhibited 3',5'-cyclic phosphodiesterase A (PDE3A)., Conclusions: Cardiac surgery with CPB resulted in inflammasome changes accompanied by unexpected increases in metabolic pathways. In exploratory analyses, we found that POD was associated with changes in the expression level of various proteins, most notably IL-6 and PDE3A. This study and ongoing protein biomarker studies will likely help quantify risk or confirm the diagnosis for POD and increase understanding of its pathophysiological mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rhee, Kuznetsov, McKay, Lyons, Houstis, Mekkonen, Ethridge, Ibala, Hahm, Gitlin, Guseh, Kitchen, Rosenzweig, Shaefi, Flaczyk, Qu and Akeju.)

Importance: Population-specific normative data are essential for the evaluation of competitive athletes. At present, there are limited data defining normal electrocardiographic (ECG) and echocardiographic values among elite US soccer players., Objective: To describe ECG and echocardiographic findings in healthy elite US soccer players., Design, Setting, and Participants: This cross-sectional study analyzed Fédération Internationale de Football Association-mandated screening sessions performed at US Soccer National Team training locations from January 2015 to December 2019. US women's and men's national team soccer players undergoing mandated cardiovascular screening were included., Main Outcomes and Measures: Normal training-related and abnormal ECG findings were reported using the International Recommendations for Electrocardiographic Interpretation in Athletes. Echocardiographic measurements of structural and functional parameters relevant to cardiovascular remodeling were assessed relative to American Society of Echocardiography guideline-defined normal ranges., Results: A total of 238 athletes (122 [51%] female; mean [SD] age, 20 [4] years; age range, 15-40 years) were included. Male athletes demonstrated a higher prevalence of normal training-related ECG findings, while female athletes were more likely to have abnormal ECG patterns (14 [11%] vs 0 in male cohort), largely accounted for by abnormal T-wave inversions. Echocardiography revealed no pathologic findings meeting criteria for sport restriction, but athletes frequently exceeded normal ranges for structural cardiac parameters responsive to exercise-induced remodeling including body surface area-indexed left ventricular (LV) mass (58 of 113 female athletes [51%] and 67 of 114 male athletes [59%]), indexed LV volume (89 of 115 female athletes [77%] and 76 of 111 male athletes [68%]), and LV wall thickness (37 of 122 female athletes [30%] and 47 of 116 male athletes [41%]). Age-stratified analysis revealed age-dependent increases in LV wall thickness, mass, and volumes among female athletes and LV wall thickness and mass among male athletes., Conclusions and Relevance: These data represent the first set of comprehensive normative values for elite US soccer players and one of the largest sport-specific echocardiographic remodeling studies in female athletes. Abnormal ECG findings were more common in female athletes, while both female and male athletes frequently exceeded clinical normality cut points for remodeling-associated echocardiographic parameters.

Objectives: To characterize the impact of obesity on disease severity in patients with coronavirus disease 2019., Design: This was a retrospective cohort study designed to evaluate the association between body mass index and risk of severe disease in patients with coronavirus disease 2019. Data were abstracted from the electronic health record. The primary endpoint was a composite of intubation or death., Setting: Two hospitals in Massachusetts (one quaternary referral center and one affiliated community hospital)., Patients: Consecutive patients hospitalized with confirmed coronavirus disease 2019 admitted between March 13, 2020, and April 3, 2020., Interventions: None., Measurements and Main Results: A total of 305 patients were included in this study. We stratified patients by body mass index category: < 25 kg/m (54 patients, 18%), ≥ 25 kg/m to < 30 kg/m (124 patients, 41%), ≥ 30 kg/m to < 35 kg/m (58 patients, 19%), and ≥ 35 kg/m (69 patients, 23%). In total, 128 patients (42%) had a primary endpoint (119 patients [39%] were intubated and nine died [3%] without intubation). Sixty-five patients (51%) with body mass index greater than or equal to 30 kg/m were intubated or died. Adjusted Cox models demonstrated that body mass index greater than or equal to 30 kg/m was associated with a 2.3-fold increased risk of intubation or death (95% CI, 1.2-4.3) compared with individuals with body mass index less than 25 kg/m. Diabetes was also independently associated with risk of intubation or death (hazard ratio, 1.8; 95% CI, 1.2-2.7). Fifty-six out of 127 patients (44%) with body mass index greater than or equal to 30 kg/m had diabetes, and the combination of both diabetes and body mass index greater than or equal to 30 kg/m was associated with a 4.5-fold increased risk of intubation or death (95% CI, 2.0-10.2) compared with patients without diabetes and body mass index less than 25 kg/m., Conclusions: Among consecutive patients hospitalized with coronavirus disease 2019, obesity was an independent risk factor for intubation or death.

Routine endurance exercise confers numerous health benefits, and high intensity exercise may accelerate and magnify many of these benefits. To date, explanatory molecular mechanisms and the influence of exercise intensity remain poorly understood. Circulating factors are hypothesized to transduce some of the systemic effects of exercise. We sought to examine the role of exercise and exercise intensity on the human plasma proteome. We employed an aptamer-based method to examine 1,305 plasma proteins in 12 participants before and after exercise at two physiologically defined intensities (moderate and high) to determine the proteomic response. We demonstrate that the human plasma proteome is responsive to acute exercise in an intensity-dependent manner with enrichment analysis suggesting functional biological differences between the moderate and high intensity doses. Through integration of available genetic data, we estimate the effects of acute exercise on exercise-associated traits and find proteomic responses that may contribute to observed clinical effects on coronary artery disease and blood pressure regulation. In sum, we provide supportive evidence that moderate and high intensity exercise elicit different signaling responses, that exercise may act in part non-cell autonomously through circulating plasma proteins, and that plasma protein dynamics can simulate some the beneficial and adverse effects of acute exercise.

Importance: Aortic dilatation is frequently encountered in clinical practice among aging endurance athletes, but the distribution of aortic sizes in this population is unknown. It is additionally uncertain whether this may represent aortic adaptation to long-term exercise, similar to the well-established process of ventricular remodeling., Objective: To assess the prevalence of aortic dilatation among long-term masters-level male and female athletes with about 2 decades of exercise exposure., Design, Setting, and Participants: This cross-sectional study evaluated aortic size in veteran endurance athletes. Masters-level rowers and runners aged 50 to 75 years were enrolled from competitive athletic events across the United States from February to October 2018. Analysis began January 2019., Exposures: Long-term endurance exercise., Main Outcomes and Measures: The primary outcome was aortic size at the sinuses of Valsalva and the ascending aorta, measured using transthoracic echocardiography in accordance with contemporary guidelines. Aortic dimensions were compared with age, sex, and body size-adjusted predictions from published nomograms, and z scores were calculated where applicable., Results: Among 442 athletes (mean [SD] age, 61 [6] years; 267 men [60%]; 228 rowers [52%]; 214 runners [48%]), clinically relevant aortic dilatation, defined by a diameter at sinuses of Valsalva or ascending aorta of 40 mm or larger, was found in 21% (n = 94) of all participants (83 men [31%] and 11 women [6%]). When compared with published nomograms, the distribution of measured aortic size displayed a rightward shift with a rightward tail (all P < .001). Overall, 105 individuals (24%) had at least 1 z score of 2 or more, indicating an aortic measurement greater than 2 SDs above the population mean. In multivariate models adjusting for age, sex, body size, hypertension, and statin use, both elite competitor status (rowing participation in world championships or Olympics or marathon time under 2 hours and 45 minutes) and sport type (rowing) were independently associated with aortic size., Conclusions and Relevance: Clinically relevant aortic dilatation is common among aging endurance athletes, raising the possibility of vascular remodeling in response to long-term exercise. Longitudinal follow-up is warranted to establish corollary clinical outcomes in this population.

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function 1,2 . Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes 3,4 . The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion 5 . In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.

Background: Differences in proteomic profiles between men and women may provide insights into the biological pathways that contribute to known sex differences in cardiovascular disease (CVD)., Objectives: This study sought to investigate sex differences in circulating biomarkers representative of biological pathways implicated in the development of CVD among Framingham Heart Study participants., Methods: The authors measured 71 circulating CVD protein biomarkers in 7,184 participants (54% women, mean age 49 years). Multivariable models were used to evaluate the associations of sex, menopause, and hormone status with biomarkers. Cox models were used to examine whether sex modified the association of biomarkers with incident CVD., Results: Of 71 biomarkers examined, 61 (86%) differed significantly between men and women, of which 37 were higher in women (including adipokines and inflammatory markers such as leptin and C-reactive protein), and 24 were higher in men (including fibrosis and platelet markers such as MMP-8 (matrix metalloproteinase-8) and TIMP-1 (tissue inhibitor of metalloproteinases 1); false discovery rate q < 0.05 for all). Sex differences in biomarker profiles were most pronounced between pre-menopausal women versus men, with attenuated sex differences among post-menopausal women not taking hormone replacement therapy. Sex modified the association of specific biomarkers with incident CVD, including CD14 and apolipoprotein B (p interaction  <0.05 for all)., Conclusions: In a predominantly Caucasian population, the authors identified widespread sex differences in circulating biomarkers that reflect distinct pathways implicated in CVD, including inflammation, adiposity, fibrosis, and platelet homeostasis. Menopause and hormone status accounted for some, but not all, of the observed sex differences. Further investigation into factors underlying sex-based differences may provide mechanistic insight into CVD development., (Copyright © 2019 American College of Cardiology Foundation. All rights reserved.)

In a recent paper published in Cell Research, Abdul-Ghani and colleagues show that the cytokine, cardiotrophin-1 (CT1), drives a protective form of reversible cardiac hypertrophy that acts through a nonapoptotic caspase-dependent mechanism. Since CT1 can be delivered as exogenous protein, these studies provide new biological insights and potential translational opportunities.

Opinion Statement: Normal pulmonary artery pressures at rest, with an exaggerated rise during exercise, characterize exercise-induced pulmonary hypertension. Exercise itself as it relates to this condition is not deleterious, nor does it cause or induce disease. However much like any classical stress test, it is a physiologic probe that aids in disease unmasking. Although more work is required to establish criteria for defining this clinical entity, the phenomenon is real. It remains unknown whether it represents a nascent form of cardiopulmonary disease and whether its genesis predicts fulminant cardiopulmonary disease. Incremental cardiopulmonary exercise testing and the construction of pressure-flow plots to describe the pulmonary vascular response to exercise will be essential in defining this disease. The critical first step remains a consensus definition that will allow for further prospective study focused by a common language.

The airways are conduits that transport atmospheric oxygen to the distal alveolus. Normally, airway mucous cells are rare. However, diseases of the airway are often characterized by mucous metaplasia, in which there are dramatic increases in mucous cell numbers. As the Notch pathway is known to regulate cell fate in many contexts, we misexpressed the active intracellular domain of the mouse Notch1 receptor in lung epithelium. Notch misexpression resulted in an increase in mucous cells and a decrease in ciliated cells in the airway. Similarly, mouse embryonic tracheal explants and adult human airway epithelium treated with Notch agonists displayed increased mucous cell numbers and decreased ciliated cell numbers. Notch antagonists had the opposite effect. Notably, Notch antagonists blocked IL13-induced mucous metaplasia. IL13 has a well-established role as an inflammatory mediator of mucous metaplasia and functions through Stat6-mediated gene transcription. We found that Notch ligands, however, are able to cause mucous metaplasia in Stat6-null cultured trachea, thus identifying a novel pathway that stimulates mucous metaplasia. Notch signaling may therefore play an important role in airway disease and, by extension, Notch antagonists may have therapeutic value. Conversely, in the distal lung, Notch misexpression prevented the differentiation of alveolar cell types. Instead, the distal lung formed cysts composed of cells that were devoid of alveolar markers but that expressed some, but not all, markers of proximal airway epithelium. Occasional distal cystic cells appeared to differentiate into normal proximal airway cells, suggesting that ectopic Notch signaling arrests the normal differentiation of distal lung progenitors before they initiate an alveolar program.

The effects of Wnt7b on lung development were examined using a conditional Wnt7b-null mouse. Wnt7b-null lungs are markedly hypoplastic, yet display largely normal patterning and cell differentiation. In contrast to findings in prior hypomorphic Wnt7b models, we find decreased replication of both developing epithelium and mesenchyme, without abnormalities of vascular smooth muscle development. We further demonstrate that Wnt7b signals to neighboring cells to activate both autocrine and paracrine canonical Wnt signaling cascades. In contrast to results from hypomorphic models, we show that Wnt7b modulates several important signaling pathways in the lung. Together, these cascades result in the coordinated proliferation of adjacent epithelial and mesenchymal cells to stimulate organ growth with few alterations in differentiation and patterning.

A full description of the ontogeny of the beta cell would guide efforts to generate beta cells from embryonic stem cells (ESCs). The first step requires an understanding of definitive endoderm: the genes and signals responsible for its specification, proliferation, and patterning. This report describes a global marker of definitive endoderm, Claudin-6 (Cldn6). We report its expression in early development with particular attention to definitive endoderm derivatives. To create a genetic system to drive gene expression throughout the definitive endoderm with both spatial and temporal control, we target the endogenous locus with an inducible Cre recombinase (Cre-ER(T2)) cassette. Cldn6 null mice are viable and fertile with no obvious phenotypic abnormalities. We also report a lineage analysis of the fate of Cldn6-expressing embryonic cells, which is relevant to the development of the pancreas, lung, and liver.