Brian Yu

All Publications

• Clinical Impact of Routine Assessment of Patient-Reported Health Status in Heart Failure Clinic. Circulation Sandhu, A. T., Calma, J., Skye, M., Kalwani, N. M., Zheng, J., Schirmer, J., Din, N., Brown Johnson, C., Gupta, A., Lan, R., Yu, B., Spertus, J. A., Heidenreich, P. A. 2024

  Abstract

  The impact of routine clinic use of patient-reported outcome (PRO) measures on clinical outcomes in patients with heart failure (HF) has not been well-characterized. We tested if clinic-based use of a disease-specific PRO improves patient-reported quality of life at 1 year.PRO-HF was an open-label, parallel, patient-level randomized clinical trial of routine PRO assessment or usual care at an academic HF clinic between August 30, 2021, and June 30, 2022, with 1 year of follow-up. In the PRO assessment arm, participants completed the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) at each HF clinic visit and results were shared with their treating clinician. The usual care arm completed the KCCQ-12 at randomization and 1 year later, which was not shared with the treating clinician. The primary outcome was the KCCQ-12 Overall Summary Score (OSS) between 12-15 months post-randomization. Secondary outcomes included domains of the KCCQ-12, hospitalization and emergency department visit rates, HF medication therapy, clinic visit frequency, and testing rates.Across 17 clinicians, 1,248 participants were enrolled and randomized to PRO assessment (n=624) or usual care (n=624). The median age was 63.9 (interquartile range [IQR] 51.8-72.8), 38.9% were women, and the median baseline KCCQ-12 OSS was 82.3 (IQR 58.3-94.8). Final KCCQ-12 (available in 87.9% of the PRO arm and 85.1% in usual care [p=0.16]) median OSS scores were 87.5 (IQR 68.8-96.9) in the PRO arm and 87.6 (IQR 69.7-96.9) in the usual care arm with a baseline-adjusted mean difference of 0.2 (95% CI: -1.7 to 2.0; p=0.85). The results were consistent across pre-specified subgroups. A post hoc analysis demonstrated a significant interaction with greater benefit among participants with baseline KCCQ-12 OSS scores of 60-80 but not in less or more symptomatic participants. No significant differences were found in 1-year mortality, hospitalizations, ED visits, medication therapy, clinic follow-up, or testing rates between arms.Routine PRO assessment in HF clinic visits did not impact patient-reported quality of life or other clinical outcomes. Alternate strategies and settings for embedding PROs into routine clinical care should be tested.

  View details for DOI 10.1161/CIRCULATIONAHA.124.069624

  View details for PubMedID 38583147

• Impact of Patient-Reported Outcome Measurement in Heart Failure Clinic on Clinician Health Status Assessment and Patient Experience: A Sub-Study of the PRO-HF Trial. Circulation. Heart failure Sandhu, A. T., Zheng, J., Kalwani, N., Gupta, A., Calma, J., Skye, M., Lan, R., Yu, B., Spertus, J., Heidenreich, P. 2022

  Abstract

  Background: Clinicians typically estimate heart failure (HF) health status using the New York Heart Association (NYHA) class, which is often discordant with patient-reported health status. It is unknown if collecting patient-reported health status improves the accuracy of clinician assessments. Methods: The Patient-Reported Outcomes in Heart Failure Clinic (PRO-HF) trial is a randomized, non-blinded trial evaluating routine Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) collection in HF clinic. Patients with a scheduled visit to Stanford HF clinic between August 30, 2021, and June 30, 2022 were enrolled and randomized to KCCQ-12 assessment or usual care. In this prespecified sub-study, we evaluated whether access to the KCCQ-12 improved the accuracy of clinicians' NYHA assessment or patients' perspectives on their clinician interaction. We surveyed clinicians regarding their patients' NYHA class, quality of life, and symptom frequency. Clinician responses were compared with patients' KCCQ-12 responses. We surveyed patients regarding their clinician interactions. Results: Of the 1,248 enrolled patients, 1,051 (84.2%) attended a visit during the sub-study. KCCQ-12 results were given to the clinicians treating the 528 patients in the KCCQ-12 arm; the 523 patients in the usual care arm completed the KCCQ-12 without the results being shared. The correlation between NYHA class and KCCQ-12 Overall Summary Score was stronger when clinicians had access to the KCCQ-12 (r=-0.73 vs. r=-0.61, p<0.001). More patients in the KCCQ-12 arm strongly agreed that their clinician understood their symptoms (95.2% vs. 89.7% of respondents; [OR 2.27; 95% CI: 1.32-3.87)]. However, patients in both arms reported similar quality of clinician communication and therapeutic alliance. Conclusions: Collecting the KCCQ-12 in HF clinic improved clinicians' accuracy of health status assessment; correspondingly, patients believed their clinicians better understood their symptoms. Registration: URL: ClinicalTrials.gov; Unique Identifier: NCT04164004.

  View details for DOI 10.1161/CIRCHEARTFAILURE.122.010280

  View details for PubMedID 36334312

• Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity JACC: CARDIOONCOLOGY Yu, B., Osman, A. G., Sladojevic, N., Prabhu, N., Tai, H., Chen, D., Perla, G., Park, L., Larson, R. A., Liao, J. K. 2022; 4 (3): 371-383

  Abstract

  Second- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome-positive (Ph+) leukemia.We hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK).Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs.Patients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph+ leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP.Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs.

  View details for DOI 10.1016/j.jaccao.2022.06.004

  View details for Web of Science ID 000860995800011

  View details for PubMedID 36213346

  View details for PubMedCentralID PMC9537085

• Deconvoluting the Cells of the Human Heart with iPSC Technology: Cell Types, Protocols, and Uses. Current cardiology reports Yu, B., Zhao, S. R., Yan, C. D., Zhang, M., Wu, J. C. 2022

  Abstract

  PURPOSE OF REVIEW: Induced pluripotent stem cells (iPSCs) have become widely adopted tools in cardiovascular biology due to their ability to differentiate into patient-specific cell types. Here, we describe the current protocols, important discoveries, and experimental limitations from the iPSC-derived cell types of the human heart: cardiomyocytes, cardiac fibroblasts, vascular smooth muscle cells, endothelial cells, and pericytes. In addition, we also examine the progress of 3D-based cell culture systems.RECENT FINDINGS: There has been rapid advancement in methods to generate cardiac iPSC-derived cell types. These advancements have led to improved cardiovascular disease modeling, elucidation of interactions among different cell types, and the creation of 3D-based cell culture systems able to provide more physiologically relevant insights into cardiovascular diseases. iPSCs have become an instrumental model system in the toolbox of cardiovascular biologists. Ongoing research continues to advance the use of iPSCs in (1) disease modeling, (2) drug screening, and (3) clinical trials in a dish.

  View details for DOI 10.1007/s11886-022-01670-z

  View details for PubMedID 35244869

• Improvements in patient safety culture: a national Taiwanese survey, 2009-16 INTERNATIONAL JOURNAL FOR QUALITY IN HEALTH CARE Yu, B., Wen, C., Lo, H., Liao, H., Wang, P. 2020; 32 (1): A9–A17

  Abstract

  To assess national trends in patient safety culture in Taiwan.A safety attitudes questionnaire (SAQ) was distributed to 144 hospitals from 2009 to 2016 (n = 392 341).Taiwan's medical centers, regional hospitals and community hospitals.Hospital staff in Taiwan.None.5-point Likert scale to assess changes in patient safety culture dimensions (teamwork, safety climate, job satisfaction, stress recognition, management and working conditions) converted to positive response rate (percentage of respondents who answered slightly agree or strongly agree on Likert scale).Dimensions for patient safety culture significantly increased in Taiwan over a period of 8 years, with an all-composite improvement in positive response rate of 4.6% (P < 0.001). Regional hospitals and community hospitals registered an all-composite improvement of 6.7 and 7.0%, respectively, while medical centers improved by 4.0%. Improvements for regional and community hospitals primarily occurred in teamwork (regional hospitals, 10.4% [95% confidence interval [CI], 10.2-10.6]; community hospitals, 8.5% [95% CI, 8.0-9.0]) and safety climate (regional hospitals, 11.1% [95% [CI], 10.9-11.4]; community hospitals, 11.3% [95% CI, 10.7-11.8]) (P < 0.001, all differences). Compared with nurses (5.1%) and pharmaceutical staff (10.6%), physicians improved the least (2.0%). Improvements for nurses and pharmacists were driven by increases in perceptions of teamwork (nurses, 9.8% [95% CI, 9.7-10.0]; pharmaceutical staff, 14.2% [95% CI, 13.4-14.9]) and safety climate (nurses, 9.0% [95% CI, 8.8-9.1]; pharmaceutical staff, 16.4% [95% CI, 15.7-17.2]) (P < 0.001, all differences). At study end, medical centers (55.1%) had greater all-composite measurements of safety culture than regional hospitals (52.4%) and community hospitals (52.2%) while physicians (63.7%) maintained greater measurements of safety culture than nurses (52.1%) and pharmaceutical staff (56.6%).These results suggest patient safety culture improved in Taiwan from 2009 to 2016.

  View details for DOI 10.1093/intqhc/mzz099

  View details for Web of Science ID 000537406400003

  View details for PubMedID 31917449

• Targeting Rho-associated coiled-coil forming protein kinase (ROCK) in cardiovascular fibrosis and stiffening EXPERT OPINION ON THERAPEUTIC TARGETS Yu, B., Sladojevic, N., Blair, J. E., Liao, J. K. 2020; 24 (1): 47–62

  Abstract

  Introduction: Pathological cardiac fibrosis, through excessive extracellular matrix protein deposition from fibroblasts and pro-fibrotic immune responses and vascular stiffening is associated with most forms of cardiovascular disease. Pathological cardiac fibrosis and stiffening can lead to heart failure and arrythmias and vascular stiffening may lead to hypertension. ROCK, a serine/threonine kinase downstream of the Rho-family of GTPases, may regulate many pro-fibrotic and pro-stiffening signaling pathways in numerous cell types.Areas covered: This article outlines the molecular mechanisms by which ROCK in fibroblasts, T helper cells, endothelial cells, vascular smooth muscle cells, and macrophages mediate fibrosis and stiffening. We speculate on how ROCK could be targeted to inhibit cardiovascular fibrosis and stiffening.Expert opinion: Critical gaps in knowledge must be addressed if ROCK inhibitors are to be used in the clinic. Numerous studies indicate that each ROCK isoform may play differential roles in regulating fibrosis and may have opposing roles in specific tissues. Future work needs to highlight the isoform- and tissue-specific contributions of ROCK in fibrosis, and how isoform-specific ROCK inhibitors in murine models and in clinical trials affect the pathophysiology of cardiac fibrosis and stiffening. This could progress knowledge regarding new treatments for heart failure, arrythmias and hypertension and the repair processes after myocardial infarction.

  View details for DOI 10.1080/14728222.2020.1712593

  View details for Web of Science ID 000506321900001

  View details for PubMedID 31906742

• Molecular Mechanisms for Statin Pleiotropy and Possible Clinical Relevance in Cardiovascular Disease Pharmaceutical Biocatalysis: Important Enzymes, Novel Targets, and Therapies Yu, B., Sladojevic, N., Liao, J. K. Taylor & Francis. 2020; 1
• Regulator of G-Protein Signaling 5 Maintains Brain Endothelial Cell Function in Focal Cerebral Ischemia. Journal of the American Heart Association Sladojevic, N. n., Yu, B. n., Liao, J. K. 2020: e017533

  Abstract

  Background Regulator of G-protein signaling 5 (RGS5) is a negative modulator of G-protein-coupled receptors. The role of RGS5 in brain endothelial cells is not known. We hypothesized that RGS5 in brain microvascular endothelial cells may be an important mediator of blood-brain barrier function and stroke severity after focal cerebral ischemia. Methods and Results Using a transient middle cerebral artery occlusion model, we found that mice with global and endothelial-specific deletion of Rgs5 exhibited larger cerebral infarct size, greater neurological motor deficits, and increased brain edema. In our in vitro models, we observed increased Gq activity and elevated intracellular Ca2+ levels in brain endothelial cells. Furthermore, the loss of endothelial RGS5 leads to decreased endothelial NO synthase expression and phosphorylation, relocalization of endothelial tight junction proteins, and increased cell permeability. Indeed, RGS5 deficiency leads to increased Rho-associated kinase and myosin light chain kinase activity, which were partially reversed in our in vitro model by pharmacological inhibition of Gq, metabotropic glutamate receptor 1, and ligand-gated ionotropic glutamate receptor. Conclusions Our findings indicate that endothelial RGS5 plays a novel neuroprotective role in focal cerebral ischemia. Loss of endothelial RGS5 leads to hyperresponsiveness to glutamate signaling pathways, enhanced Rho-associated kinase- and myosin light chain kinase-mediated actin-cytoskeleton reorganization, endothelial dysfunction, tight junction protein relocalization, increased blood-brain barrier permeability, and greater stroke severity. These findings suggest that preservation of endothelial RGS5 may be an important therapeutic strategy for maintaining blood-brain barrier integrity and limiting the severity of ischemic stroke.

  View details for DOI 10.1161/JAHA.120.017533

  View details for PubMedID 32875943

• RELATIONSHIP BETWEEN GLOBAL LONGITUDINAL STRAIN AND LEFT VENTRICULAR DIASTOLIC FUNCTION American College of Cardiology Scientific Session 2019 Yu, B., Lin, I., Cornish, B., Lin, K., Park, L., Perla, G., Lin, S. S. 2019

  View details for DOI 10.1016/s0735-1097(19)32281-8

• Rho-Associated Kinase Activity Correlates With the Presence of Diastolic Dysfunction in Patients With Normal Left Ventricular Ejection Fraction American Heart Association Scientific Session 2019 Yu, B., Al Kassem, H., Ma, L., Allan, T., Dryer, K., Park, L., Malwankar, J., Perla, G., Blair, J. E., Liao, J. K. 2019
• ABL Tyrosine Kinase Inhibitors (TKIs) Are Associated with Increased Rho-Associated Kinase (ROCK) Activity That May Contribute to Vascular Toxicity in Patients with Chronic Myeloid Leukemia (CML) American Society of Hematology Annual Meeting 2018 Osman, A., Yu, B., Glavin, N., Polonsky, T. S., Liao, J. K., Larson, R. A. 2018

  View details for DOI 10.1182/blood-2018-99-111201

• THE FEASIBILITY OF GLOBAL LONGITUDINAL STRAIN IN CLINICAL PRACTICE AND RELATIONSHIP WITH EJECTION FRACTION Yu, B., Lin, I., Boyd, H., Winchester, S., Caldwell, E., Lin, K., Cornish, B., Lin, S. S. 2018

  View details for DOI 10.1016/S0735-1097(18)32257-5

• Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction JCI INSIGHT Shimizu, T., Narang, N., Chen, P., Yu, B., Knapp, M., Janardanan, J., Blair, J., Liao, J. K. 2017; 2 (13)

  Abstract

  Although left ventricular (LV) diastolic dysfunction is often associated with hypertension, little is known regarding its underlying pathophysiological mechanism. Here, we show that the actin cytoskeletal regulator, Rho-associated coiled-coil containing kinase-2 (ROCK2), is a critical mediator of LV diastolic dysfunction. In response to angiotensin II (Ang II), mutant mice with fibroblast-specific deletion of ROCK2 (ROCK2Postn-/-) developed less LV wall thickness and fibrosis, along with improved isovolumetric relaxation. This corresponded with decreased connective tissue growth factor (CTGF) and fibroblast growth factor-2 (FGF2) expression in the hearts of ROCK2Postn-/- mice. Indeed, knockdown of ROCK2 in cardiac fibroblasts leads to decreased expression of CTGF and secretion of FGF2, and cardiomyocytes incubated with conditioned media from ROCK2-knockdown cardiac fibroblasts exhibited less hypertrophic response. In contrast, mutant mice with elevated fibroblast ROCK activity exhibited enhanced Ang II-stimulated cardiac hypertrophy and fibrosis. Clinically, higher leukocyte ROCK2 activity was observed in patients with diastolic dysfunction compared with age- and sex-matched controls, and correlated with higher grades of diastolic dysfunction by echocardiography. These findings indicate that fibroblast ROCK2 is necessary to cause cardiac hypertrophy and fibrosis through the induction CTGF and FGF2, and they suggest that targeting ROCK2 may have therapeutic benefits in patients with LV diastolic dysfunction.

  View details for DOI 10.1172/jci.insight.93187

  View details for Web of Science ID 000405181200011

  View details for PubMedID 28679962

  View details for PubMedCentralID PMC5499369

• ROCK as a therapeutic target for ischemic stroke EXPERT REVIEW OF NEUROTHERAPEUTICS Sladojevic, N., Yu, B., Liao, J. K. 2017; 17 (12): 1167–77

  Abstract

  Stroke is a major cause of disability and the fifth leading cause of death. Currently, the only approved acute medical treatment of ischemic stroke is tissue plasminogen activator (tPA), but its effectiveness is greatly predicated upon early administration of the drug. There is, therefore, an urgent need to find new therapeutic options for acute stroke. Areas covered: In this review, we summarize the role of Rho-associated coiled-coil containing kinase (ROCK) and its potential as a therapeutic target in stroke pathophysiology. ROCK is a major regulator of cell contractility, motility, and proliferation. Many of these ROCK-mediated processes in endothelial cells, vascular smooth muscle cells, pericytes, astrocytes, glia, neurons, leukocytes, and platelets are important in stroke pathophysiology, and the inhibition of such processes could improve stroke outcome. Expert commentary: ROCK is a potential therapeutic target for cardiovascular disease and ROCK inhibitors have already been approved for human use in Japan and China for the treatment of acute stroke. Further studies are needed to determine the role of ROCK isoforms in the pathophysiology of cerebral ischemia and whether there are further therapeutic benefits with selective ROCK inhibitors.

  View details for DOI 10.1080/14737175.2017.1395700

  View details for Web of Science ID 000416022100005

  View details for PubMedID 29057688

  View details for PubMedCentralID PMC6221831