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The use of computer-aided methods have continued to propel accelerated drug discovery across various disease models, interestingly allowing the specific inhibition of pathogenic targets. Chloride Intracellular Channel Protein 4 (CLIC4) is a novel class of intracellular ion channel highly implicated in tumor and vascular biology. It regulates cell proliferation, apoptosis and angiogenesis; and is involved in multiple pathologic signaling pathways. Absence of specific inhibitors however impedes its advancement to translational research. Here, we integrate structural bioinformatics and experimental research approaches for the discovery and validation of small-molecule inhibitors of CLIC4. High-affinity allosteric binders were identified from a library of 1615 Food and Drug Administration (FDA)-approved drugs via a high-performance computing-powered blind-docking approach, resulting in the selection of amphotericin B and rapamycin. NMR assays confirmed the binding and conformational disruptive effects of both drugs while they also reversed stress-induced membrane translocation of CLIC4 and inhibited endothelial cell migration. Structural and dynamics simulation studies further revealed that the inhibitory mechanisms of these compounds were hinged on the allosteric modulation of the catalytic glutathione (GSH)-like site loop and the extended catalytic β loop which may elicit interference with the catalytic activities of CLIC4. Structure-based insights from this study provide the basis for the selective targeting of CLIC4 to treat the associated pathologies., Competing Interests: None., (Crown Copyright © 2023 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.)

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sustained pulmonary vasoconstriction and concentric pulmonary vascular remodeling contribute to the elevated pulmonary vascular resistance and pulmonary artery pressure in PAH. Endothelial cells regulate vascular tension by producing endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs). Homeostasis of EDRF and EDCF production has been identified as a marker of the endothelium integrity. Impaired synthesis or release of EDRFs induces persistent vascular contraction and pulmonary artery remodeling, which subsequently leads to the development and progression of PAH. In this review, the authors summarize how EDRFs and EDCFs affect pulmonary vascular homeostasis, with special attention to the recently published novel mechanisms related to endothelial dysfunction in PAH and drugs associated with EDRFs and EDCFs., Competing Interests: This work was funded in part by the National Key Research and Development Program of China (grant 2019YFE0119400), the Natural Science Foundation of China (grants 81970052 and 82170057), and the National Lung, Heart, and Blood Institute of the National Institutes of Health (grant R35 HL135807). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Objective: Systemic sclerosis (SSc) related mortality and morbidity remains high. Immunosuppressive therapy is considered most effective when immune activity and inflammation but not fibrosis still dominates the disease process. This study evaluated long-term intensified immunosuppression combined with therapeutic plasma exchange (TPE) in early-onset progressive SSc-related interstitial lung disease (ILD)., Methods: The study cohort consisted of 161 SSc patients, with a median follow-up time of 8.9 years. The standardized mortality rate (SMR) and overall survival was calculated in patients with and without cardiopulmonary involvement. We used a standardized, pragmatic, non-randomized approach to treat 24 consecutive early progressive SSc-ILD patients with intensified immunosuppressive therapy, including plasma exchange. Outcome measurements were event-free survival (EFS), pulmonary function and safety profile. The outcome was compared with the analyzed data from the other SSc-ILD patients, who did not fulfill the inclusion criteria, and instead were treated with estimated optimal care (EOc)., Results: The age-adjusted SMR of all 161 SSc patients was 3.0 (CI95%; 0.32-5.68). EFS at 10 years was 49.9% in the intensified treatment group and 43.3% in the EOc group (p = 0.106). Improvement of the percentage of predicted forced vital capacity (%pFVC) and percentage of predicted diffusing capacity for carbon monoxide (%pDLco) in the intensified treatment group was +10.1% respectively +3.6%, compared to a decrease of respectively 10.8% and 7% in the EOc (p < 0.001 resp. p = 0.019). Safety analysis showed 1 death (female patient, over 75 years of age), due to pneumosepsis, in the intensified treatment group., Conclusion: Intensified and long-lasting immunosuppression combined with TPE is safe in early severe systemic sclerosis and is associated with improved EFS and pulmonary function as compared to the outcome in the variable but EOc group. Our findings warrant larger studies for confirmation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Mortality after repair of total anomalous pulmonary venous drainage (TAPVD) in neonates has remained high. Analysis of risk factors may help identify therapeutic targets to improve survival., Methods: Retrospective analysis of all neonates who underwent simple TAPVD repair., Results: Between 1973 and 2021, 175 neonates underwent TAPVD repair, at a median age of 6 days (interquartile range, 2-15 days) and a mean weight of 3.2 ± 0.6 kg. TAPVD was supracardiac in 42.3% of the patients (74 of 175), cardiac in 14.3% (25 of 175), infracardiac in 40% (70 of 175), and mixed type in 3.4% (6 of 175), with obstruction in 65.7% (115 of 175). Pulmonary hypertension (PHT) crisis occurred in 12% (21 of 175). Early mortality was 9.7% (17 of 175) and late mortality was 5.1% (8 of 158), with most deaths occurring within 1 year (75%; 6 of 8). Survival was 86.5% (95% CI, 80.3%-90.8%) at 1 year and 85.8% (95% CI, 79.6%-90.3%) at 5, 10, 15, and 20 years. Survival was lower in patients with obstructed TAPVD, patients with emergent surgery, and those with PHT crisis. PHT crisis (hazard ratio [HR], 4.93; 95% CI, 1.95-12.51; P  = .001), urgency of surgery (HR, 2.51; 95% CI, 1.11-5.68; P  = .027), and higher pulmonary artery pressure-to-systemic blood pressure percentage ratio (HR, 1.06; 95% CI, 1.01-1.11; P  = .026) were identified as risk factors for mortality. Histopathological analysis of 17 patients (9.7%; 17 of 175) showed signs of pulmonary arterial hypertension with media hypertrophy in 58.8% (10 of 17)., Conclusions: Mortality after TAPVD repair occurred mainly within the first year of life. Urgency of surgery and persistent PHT appears to be risk factors for mortality. Lung biopsy might be useful for identifying patients at risk and guiding newer treatment modalities., (© 2022 The Authors. Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery.)

Competing Interests: The authors declare that there is no conflict of interest.

Background: The Saudi Food and Drug Authority (SFDA) requires marketing authorization holders to submit a PIL in both Arabic and English language. However, the readability of imprinted and disseminated Patient information leaflets (PILs) was not assessed extensively in Saudi Arabia. This study aims to assess the readability of PIL of antihypertensive drugs in both Arabic and English languages., Method: This study was a descriptive quantitative analysis conducted in Saudi Arabia in August 2021. PILs of all oral antihypertensive medications in Saudi Arabia were included in the study. The Arabic and English PILs were extracted from the Saudi Drugs Information System (SDI) and pharmaceutical companies' registration documents. The study used Flesch-Kincaid grade level to assess the readability of English and sentence length to assess the Arabic texts. Descriptive analyses were used to assess the readability scores and the mean differences., Results: It was found that almost 88% of English PILs were above recommended readability level compared to 79% of Arabic PILs. About 89% of English PILs of generic and 86% of brand-name medications were above the readability cutoff point compared with 83% of Arabic PILs of generic and 68% of brand-name medications. The means of grade level for readability of PILs for the widely used antihypertensive medications including angiotensin II receptor blockers (ARBs), antiadrenergic, diuretics, Beta-blockers (BBs), calcium channel blockers (CCBs), and combination antihypertensive medications, and CCBs were higher than the recommended readability level ( p < 0.05). The highest mean grade level for readability among English PILs was for combinations of antihypertensive agents (9.35 ± 1.38, p 0.01) and among Arabic PILs was for ARBs (6.15 ± 1.62, p < 0.01)., Conclusions: The majority of PILs of antihypertensive medications were above the recommended readability level that can be understood by the majority of the public, especially among generic medications and the most widely used antihypertensive medications. The study findings highlight the need of implementing guidelines to improve the readability of information imprinted in PILs and adopt new regulations requiring readability assessment for manufactures before submitting the PILs to the SFDA., (© 2022 The Authors.)

Pulmonary hypertension (PH) is caused by a range of conditions and is important to recognize as it is associated with increased mortality. Pulmonary arterial hypertension refers to a group of PH subtypes affecting the distal pulmonary arteries for which effective treatment is available. The hemodynamic definition of pulmonary arterial hypertension has recently changed which may lead to greater case recognition and earlier treatment. The prevalence of specific PH etiologies may differ depending on geographic region. PH caused by left heart disease is the most common cause of PH worldwide. In Asia, there is greater proportion of congenital heart disease- and connective tissue disease- (especially systemic lupus erythematosus) related PH relative to the West. This review summarizes the definition, classification, and epidemiology of PH as it pertains to Asia., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: The time-velocity integral of the left ventricular outflow tract (TVI LVOT ) has been demonstrated to correlate with heart failure hospitalization and mortality, but the association of TVI LVOT with the severity and prognosis of pulmonary arterial hypertension (PAH) has not been evaluated., Objectives: The aim of this study was to investigate the predictive value of baseline TVI LVOT in PAH., Methods: A total of 225 consecutive patients with a diagnosis of incident PAH were prospectively studied and echocardiology-derived TVI LVOT was measured at enrollment followed by right heart catheterization examination within 48 hours. Cox proportional hazards analysis was performed to assess the association between baseline variables and mortality., Results: During a median follow-up period of 33.8 months, 44 patients died of cardiovascular events. Baseline TVI LVOT was significantly lower in the nonsurvivors compared with the survivors ( P  < 0.001). Baseline TVI LVOT was positively correlated with stroke volume obtained by right heart catheterization ( r  = 0.709; P  < 0.001), and inversely correlated with N-terminal pro-B-type natriuretic peptide ( r = -0.533; P  < 0.001), pulmonary vascular resistance ( r = -0.423; P  < 0.001). Multivariate analysis showed that baseline TVI LVOT (hazard ratio: 0.856; 95% CI: 0.780-0.941; P  = 0.001) was an independent predictor of cardiovascular mortality in PAH. Patients with a baseline TVI LVOT  <17.1 cm (median value) had a significantly worse survival than those with a baseline TVI LVOT  ≥17.1 cm ( P  < 0.001)., Conclusions: The findings of this study suggest that noninvasive TVI LVOT provides a practical method to assess the severity and predict long-term outcome of PAH., Competing Interests: This work was supported by the National Key Research and Development Program of China grant No. 2016YFC0901502 (Dr Xu). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Pulmonary hypertension is a disabling and life-threatening cardiovascular disease. Early detection of elevated pulmonary artery pressure (ePAP) is needed for prompt diagnosis and treatment to avoid detrimental consequences of pulmonary hypertension., Objectives: This study sought to develop an artificial intelligence (AI)-enabled electrocardiogram (ECG) model to identify patients with ePAP and related prognostic implications., Methods: From a hospital-based ECG database, the authors extracted the first pairs of ECG and transthoracic echocardiography taken within 2 weeks of each other from 41,097 patients to develop an AI model for detecting ePAP (PAP > 50 mm Hg by transthoracic echocardiography). The model was evaluated on independent data sets, including an external cohort of patients from Japan., Results: Tests of 10-fold cross-validation neural-network deep learning showed that the area under the receiver-operating characteristic curve of the AI model was 0.88 (sensitivity 81.0%; specificity 79.6%) for detecting ePAP. The diagnostic performance was consistent across age, sex, and various comorbidities (diagnostic odds ratio >8 for most factors examined). At 6-year follow-up, the patients predicted by the AI model to have ePAP were independently associated with higher cardiovascular mortality (HR: 3.69). Similar diagnostic performance and prediction for cardiovascular mortality could be replicated in the external cohort., Conclusions: The ECG-based AI model identified patients with ePAP and predicted their future risk for cardiovascular mortality. This model could serve as a useful clinical test to identify patients with pulmonary hypertension so that treatment can be initiated early to improve their survival prognosis., Competing Interests: This work was supported by Taipei Veterans General Hospital (VGH108C-019, VN108-12, VN109-03, V109C-070, V110C-039, V110B-043, V111C-047, VGHUST111-G6-3-2, VTA111-A-1-2), Ministry of Science and Technology (MOST 108-2628-B-075-003, MOST 109-2628-B-075-017, MOST 110-2628-B-075-015, MOST 110-2314-B-075-063-MY3, MOST 110-2321-B-075-002), Szu-Yuan Research Foundation of Internal Medicine (107-041), National Health Research Institutes (NHRI-EX108-10513SC, NHRI-109BCC0-MF-202014-02), and Academia Sinica (AS-TM-109-01-05, AS-TM-110-01-01). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Pulmonary arterial hypertension (PAH) is a rare, progressive disease. The treatment landscape for PAH in Japan has evolved considerably in recent years, but there is limited knowledge of the changes in treatment practices or patient characteristics., Objectives: The aim of this study was to evaluate the changes in characteristics and initial treatments for PAH in Japan over time., Methods: This study used data from the Japan Pulmonary Hypertension Registry (JAPHR) to compare patient characteristics and treatment practices between 2008-2015 (n = 316) and 2016-2020 (n = 315)., Results: The mean ± standard deviation age at diagnosis increased from 47.9 ± 16.7 years in 2008-2015 to 52.7 ± 16.9 years in 2016-2020. The mean pulmonary arterial pressure decreased from 45.4 ± 15.0 to 38.6 ± 13.1 mm Hg. Idiopathic/hereditary PAH was the most common etiology in both periods (50.0% and 51.1%, respectively). The proportion of patients prescribed oral/inhaled combination therapies increased from 47.8% to 57.5%. Oral/inhaled combination therapies were frequently prescribed to patients with congenital heart disease-related PAH (81.8%). There was no significant trend in prescribing practices based on French low-risk criteria: among patients with 0, 1, 2, 3, or 4 criteria, 53.8%, 68.8%, 52.8%, 66.7%, and 39.4% were prescribed oral/inhaled combination therapies, and 0%, 16.7%, 27.0%, 17.3%, and 15.2% were prescribed oral/inhaled monotherapies. Macitentan, tadalafil, selexipag, and epoprostenol were the most frequently prescribed drugs., Conclusions: The severity of PAH decreased over time in Japan. Oral/inhaled combination therapies were generally preferred. Physicians generally prescribed therapies after considering the patients' hemodynamics and clinical severity. (Japan Pulmonary Hypertension Registry [JAPHR]; UMIN000026680)., Competing Interests: This study was funded by a Health Labor Sciences Research Grant, Japan and AMED under grant number JP18lk1601003h0001. The funding body contributed to study design and data collection. Editorial support was funded by Janssen Pharmaceutical. Dr Tamura has received remuneration from Janssen and Daiichi Sankyo; research funds from Mochida; and is affiliated with the Pulmonary Hypertension Center, which is supported by an endowment from Nippon Shinyaku. Dr Kumamaru, Dr Miyata, and Ms Nishimura are affiliated with the Department of Health Quality Assessment at the University of Tokyo, a social collaboration department supported by the National Clinical Database, Johnson & Johnson, and Nipro. Dr Miyata is also affiliated with the Department of Health Policy and Management School of Medicine at Keio University that is conducting joint research with the National Clinical Database. Dr Matsubara has received remuneration from Janssen, Bayer, Pfizer Japan, Nippon Shinyaku, Kaneka Medix, GlaxoSmithKline, United Therapeutics, and Mochida; and research funds from Nippon Shinyaku. Dr Hirata has received remuneration from Takeda and Kowa; commissioned, joint, or physician-led research with Daiichi Sankyo, Janssen, Sysmex, and Terumo; scholarship donations from Merck Sharp & Dohme, Janssen, Abbott, Otsuka, Kowa, Sanofi, Takeda, Toa Eiyo, Nippon Shinyaku, Nippon Boehringer Ingelheim, Nihon Medi-Physics, Novartis, Bayer, Biotronik, and Fujifilm Toyama Chemical; and is affiliated with the Division of Cardiovascular Medicine Department of Internal Medicine, which is supported by endowments from Abbott, Medtronic, and Sysmex. Dr Tsujino has received remuneration from Nippon Shinyaku and Janssen; and is affiliated with the First Department of Medicine, which is supported by endowments from Nippon Shinyaku, Nippon Boehringer Ingelheim, and Mochida. Dr Suda is affiliated with the Department of Respirology, which is supported by endowments from Nippon Shinyaku and Janssen. Dr Tatsumi has received remuneration from Janssen. Mr Sigel and Mr Takano are employees of Janssen Pharmaceutical. Dr Inami has reported that he has no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Indigo naturalis, a herbal medicine purified from indigo-containing plants, such as Strobilanthes cusia, Isatis tinctoria, and Polygonum tinctorium , has been reported to be useful in the treatment of ulcerative colitis by activating the aryl hydrocarbon receptor. However, the aryl hydrocarbon receptor pathway causes crucial side effects, such as pulmonary arterial hypertension. Although P. tinctorium is one of the plant derivatives of indigo naturalis, it is not identical to it . To date, the pure leaves of P. tinctorium have not been reported to ameliorate ulcerative colitis. Therefore, we investigated the effect of pure P. tinctorium leaves, which are consumed in some regions, on experimental colitis induced in mice using sodium dextran sulfate. We found that P. tinctorium leaves ameliorated weight loss (P < 0.01) and pathological inflammatory changes in the colon (P < 0.05), enhanced mRNA expression of interleukin-10 (P < 0.05), and decreased expression of tumor necrosis factor-in colonic tissues (P < 0.05), as determined using quantitative real-time reverse transcription polymerase chain reaction. The intraperitoneal administration of an aryl hydrocarbon receptor antagonist did not antagonize the inhibition of mucosal destruction, whereas an anti-interleukin-10 receptor antibody did. These results suggest that P. tinctorium ameliorate sodium dextran sulfate-induced intestinal inflammation via interleukin-10-related pathway, independent of the aryl hydrocarbon receptor pathway. P. tinctorium leaves have the potential to be a new, safe treatment for ulcerative colitis., Competing Interests: The authors declare no conflicts of interest associated with this manuscript., (© 2022 The Authors.)

Purpose: Sarcopenia is closely associated with postoperative prognosis in patients undergoing cardiovascular surgery. Growth differentiation factor (GDF)-15 is involved in the pathogenesis of cardiovascular disease. We examined the relationship between the serum GDF-15 concentration and muscle function in patients receiving aortic valve replacement and healthy elderly subjects., Methods: Forty-three female patients undergoing aortic valve surgery (79.9 ± 6.4 years; transcatheter aortic valve replacement [TAVR] n = 19, conventional surgical aortic valve replacement [SAVR] n = 24) and 64 healthy elderly female subjects (75.9 ± 6.1 years) were included. Walking speed, grip strength, and skeletal muscle mass index (SMI) by a multifrequency bioelectrical impedance analyzer were measured to determine the presence of sarcopenia. Preoperative serum GDF-15 concentration was measured by enzyme-linked immunosorbent assay., Results: The GDF-15 level was higher in patients receiving aortic valve replacement than in healthy elderly subjects (aortic valve replacement: 1624 ± 1186 pg/mL vs. healthy: 955 ± 368 pg/mL, p < 0.001). Multivariate linear regression analysis showed that the serum GDF-15 level determined grip strength independently of the high-sensitivity C-reactive protein level and eGFR, even after adjusting for age (β = -0.318, p = 0.025). Sarcopenia was found in 12.5% of healthy elderly subjects, 83.3% of patients with TAVR, and 64.3% of patients with SAVR. The GDF-15 concentration that defined sarcopenia was 1109 pg/mL in subjects including patients receiving aortic valve replacement., Conclusions: The preoperative serum GDF-15 concentration, which was higher in female patients receiving aortic valve replacement than in healthy elderly subjects, may be a serum marker of sarcopenia., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

The authors show that increased poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) and pyruvate kinase muscle isozyme 2 (PKM2) expression is a common feature of a decompensated right ventricle in patients with pulmonary arterial hypertension and animal models. The authors find in vitro that overactivated PARP1 promotes cardiomyocyte dysfunction by favoring PKM2 expression and nuclear function, glycolytic gene expression, activation of nuclear factor κB-dependent proinflammatory factors. Pharmacologic and genetic inhibition of PARP1 or enforced tetramerization of PKM2 attenuates maladaptive remodeling improving right ventricular (RV) function in multiple rodent models. Taken together, these data implicate the PARP1/PKM2 axis as a critical driver of maladaptive RV remodeling and a new promising target to directly sustain RV function in patients with pulmonary arterial hypertension., Competing Interests: This research was supported by a grant from the Cardiovascular Medical Research and Education Fund to Drs Boucherat and Provencher. Dr Boucherat has been funded by the Canadian Institute of Health Research (IC121617). Dr Boucherat holds a junior scholar award from Fonds de Recherche du Québec: Santé. Dr Bonnet holds a distinguished research scholar from Fonds de Recherche du Québec: Santé. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies Δ G FEP between ligands and their target, which were more consistent with the experimental binding potencies Δ G EXP (the mean absolute deviations | Δ G FEP - Δ G EXP |  < 2 kcal/mol) than those Δ G MM-PBSA or Δ G MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC 50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

The low-density lipoprotein receptor (LDLR) gene family includes LDLR, very LDLR, and LDL receptor-related proteins (LRPs) such as LRP1, LRP1b (aka LRP-DIT), LRP2 (aka megalin), LRP4, and LRP5/6, and LRP8 (aka ApoER2). LDLR family members constitute a class of closely related multifunctional, transmembrane receptors, with diverse functions, from embryonic development to cancer, lipid metabolism, and cardiovascular homeostasis. While LDLR family members have been studied extensively in the systemic circulation in the context of atherosclerosis, their roles in pulmonary arterial hypertension (PAH) are understudied and largely unknown. Endothelial dysfunction, tissue infiltration of monocytes, and proliferation of pulmonary artery smooth muscle cells are hallmarks of PAH, leading to vascular remodeling, obliteration, increased pulmonary vascular resistance, heart failure, and death. LDLR family members are entangled with the aforementioned detrimental processes by controlling many pathways that are dysregulated in PAH; these include lipid metabolism and oxidation, but also platelet-derived growth factor, transforming growth factor β1, Wnt, apolipoprotein E, bone morpohogenetic proteins, and peroxisome proliferator-activated receptor gamma. In this paper, we discuss the current knowledge on LDLR family members in PAH. We also review mechanisms and drugs discovered in biological contexts and diseases other than PAH that are likely very relevant in the hypertensive pulmonary vasculature and the future care of patients with PAH or other chronic, progressive, debilitating cardiovascular diseases., Competing Interests: Dr Herz was supported by grants from the National Heart, Lung, and Blood Institute (R37 HL063762), the National Institute on Aging (RF AG053391), the National Institute on Neurological Disorders and Stroke and National Institute on Aging (R01 NS093382), and BrightFocus (A2016396S); the Bluefield Project to Cure FTD; and a Harrington Scholar Innovator Award (2019). Dr Hansmann has received financial support from the German Research Foundation (HA4348/2-2 and HA4348/6-2 KFO311), the Federal Ministry of Education and Research (BMBF ViP+ program-03VP08053; BMBF 01KC2001B), and the European Pediatric Pulmonary Vascular Disease Network. Dr Calvier and Dr Herz are shareholders of Reelin Therapeutics and co-inventors of a patent related to anti-Reelin strategies (application number 15/763,047 and publication number 20180273637). Dr Hansmann has reported that he has no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed., Competing Interests: This workshop was supported by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institutes of Health (NIH) Office of the Director. Dr Ajijola is supported by NIH grants DP2 OD024323, OT2 OD028201, and OT2 OD023848, Dr Chen was supported by NIH grants OT2 OD028190, R01 HL139829, and the Burns & Allen Chair in Cardiology Research, Cedars-Sinai Medical Center. Dr Clancy has received research funding from NIH grants OT2 OD026580, OT2 OD026580, R01 HL152681, R01 HL128170, and U01 HL126273, InCarda Therapeutics, and the Department of Physiology and Membrane Biology Research Partnership Fund, Oracle cloud for research allocation. Dr Delisle is supported by NIH grants R01 HL153042, R01 HL141343, and the American Heart Association grant 20IPA35320141. Dr Habecker was supported by NIH grants R01 HL093056 and R01 HL146822. Dr Handoko has received an educational grant from Novartis and Boehringer Ingelheim. Dr Redline has received research funding from NIH grants R35 HL135818, R01 HL133684, U10 HD036801, R01 HL137234, R01 DK118736, R01 AG056331, and U24 HL140412, and Jazz Pharmaceuticals. Dr Ripplinger is supported in part by research funding from NIH grants OT2 OD026580, R01 HL093056, and R01 HL111600. Dr Somers is supported by NIH grants R01 HL065176 and R01 HL134885. Dr Stavrakis was supported by NIH grant R21 AG057879. Dr Taylor-Clark is supported by NIH grants R01 HL152219, U01 NS113868, OT2 OD023854, R21 DK124894, R01 DK110366, and U01 DK110366. Dr Undem is supported by NIH grant R35 HL155671. Dr Zucker has received support from Sorrento Therapeutics, Inc. and from NIH grant R01 HL126796. Dr Shivkumar is supported by NIH grants OT2 OD028201 and OT2 OD023848. Dr Ajijola is a cofounder and equity holder of NeuCures; has served as a consultant for Merck and Biosense-Webster Inc. Dr Gold has received clinical trial research funding from Boston Scientific and Medtronic; and has been a consultant for Boston Scientific, CVRx. and Medtronic. Dr Habecker is a co-inventor of a technology (intracellular sigma peptide) that Oregon Health and Science University has licensed to NervGen Pharma Corp. Dr Handoko has received research funding from Vifor Pharma; and has been a consultant for Novartis, Boehringer Ingelheim, Vifor Pharma, AstraZeneca, Bayer, MSD, Daiichi Sankyo, and Quin. Dr Hummel has been a scientific advisory board member; and holds equity in Nuvaira, Inc. Dr Redline has received consulting fees from Jazz Pharmaceuticals and Apnimed Inc. Dr Redline has received research funding from Jazz Pharmaceuticals. Dr Somers has served as a consultant for Bayer, Respicardia, Baker Tilly, and Jazz Pharmaceuticals; and has served on the scientific advisory board of the Sleep Number Corporation. Dr Shivkumar is a cofounder and equity holder of NeuCures Inc. Dr Simon is supported in part by NIH grant R01 AG058659, serves on a clinical trial steering committee for Janssen, and has consulted for Acceleron and Bial. Dr Mehra is supported by NIH grants U01HL125177, UH3HL140144 and the American Heart Association AHA 18SFRN34170013. Dr Arora is supported by NIH grants R01 HL140061, R01 HL125881, Technology Development Program, NIH Center for Accelerated Innovations at Cleveland Clinic, the American Heart Association Strategically Focused Research Networks Atrial Fibrillation Center, and has ownership interest in Rhythm Therapeutics, Inc. Dr Handoko is supported by the Dutch Heart Foundation (Senior Clinical Scientist grant 2020T058); has received research funding from Vifor Pharma; and has been a consultant for Novartis, Boehringer Ingelheim, Vifor Pharma, AstraZeneca, Bayer, MSD, Daiichi Sankyo, and Quin. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)