Stanford Advisors

All Publications

  • Cysteine-rich with EGF-like domains 2 (CRELD2) is an endoplasmic reticulum stress-inducible angiogenic growth factor promoting ischemic heart repair NATURE CARDIOVASCULAR RESEARCH Wu, X., Zheng, L., Reboll, M. R., Hyde, L. F., Mass, E., Niessen, H. W., Kosanke, M., Pich, A., Giannitsis, E., Tillmanns, J., Bauersachs, J., Heineke, J., Wang, Y., Korf-Klingebiel, M., Polten, F., Wollert, K. C. 2024
  • Lnc-ing epicardium-derived cells to cardiac remodelling: lncRNA-TARID as a novel antifibrotic option. European heart journal Wu, X., Vacante, F., Wu, J. C. 2023

    View details for DOI 10.1093/eurheartj/ehad058

    View details for PubMedID 36928295

  • Meteorin-like promotes heart repair through endothelial KIT receptor tyrosine kinase. Science (New York, N.Y.) Reboll, M. R., Klede, S., Taft, M. H., Cai, C. L., Field, L. J., Lavine, K. J., Koenig, A. L., Fleischauer, J., Meyer, J., Schambach, A., Niessen, H. W., Kosanke, M., van den Heuvel, J., Pich, A., Bauersachs, J., Wu, X., Zheng, L., Wang, Y., Korf-Klingebiel, M., Polten, F., Wollert, K. C. 2022; 376 (6599): 1343-1347


    Effective tissue repair after myocardial infarction entails a vigorous angiogenic response, guided by incompletely defined immune cell-endothelial cell interactions. We identify the monocyte- and macrophage-derived cytokine METRNL (meteorin-like) as a driver of postinfarction angiogenesis and high-affinity ligand for the stem cell factor receptor KIT (KIT receptor tyrosine kinase). METRNL mediated angiogenic effects in cultured human endothelial cells through KIT-dependent signaling pathways. In a mouse model of myocardial infarction, METRNL promoted infarct repair by selectively expanding the KIT-expressing endothelial cell population in the infarct border zone. Metrnl-deficient mice failed to mount this KIT-dependent angiogenic response and developed severe postinfarction heart failure. Our data establish METRNL as a KIT receptor ligand in the context of ischemic tissue repair.

    View details for DOI 10.1126/science.abn3027

    View details for PubMedID 35709278

    View details for PubMedCentralID PMC9838878

  • Myeloid-Derived Growth Factor Protects Against Pressure Overload-Induced Heart Failure by Preserving Sarco/Endoplasmic Reticulum Ca2+-ATPase Expression in Cardiomyocytes. Circulation Korf-Klingebiel, M., Reboll, M. R., Polten, F., Weber, N., Jäckle, F., Wu, X., Kallikourdis, M., Kunderfranco, P., Condorelli, G., Giannitsis, E., Kustikova, O. S., Schambach, A., Pich, A., Widder, J. D., Bauersachs, J., van den Heuvel, J., Kraft, T., Wang, Y., Wollert, K. C. 2021; 144 (15): 1227-1240


    Inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Inflammatory cells secrete MYDGF (myeloid-derived growth factor) to promote tissue repair after acute myocardial infarction. We hypothesized that MYDGF has a role in cardiac adaptation to persistent pressure overload.We defined the cellular sources and function of MYDGF in wild-type (WT), Mydgf-deficient (Mydgf-/-), and Mydgf bone marrow-chimeric or bone marrow-conditional transgenic mice with pressure overload-induced heart failure after transverse aortic constriction surgery. We measured MYDGF plasma concentrations by targeted liquid chromatography-mass spectrometry. We identified MYDGF signaling targets by phosphoproteomics and substrate-based kinase activity inference. We recorded Ca2+ transients and sarcomere contractions in isolated cardiomyocytes. Additionally, we explored the therapeutic potential of recombinant MYDGF.MYDGF protein abundance increased in the left ventricular myocardium and in blood plasma of pressure-overloaded mice. Patients with severe aortic stenosis also had elevated MYDGF plasma concentrations, which declined after transcatheter aortic valve implantation. Monocytes and macrophages emerged as the main MYDGF sources in the pressure-overloaded murine heart. While Mydgf-/- mice had no apparent phenotype at baseline, they developed more severe left ventricular hypertrophy and contractile dysfunction during pressure overload than WT mice. Conversely, conditional transgenic overexpression of MYDGF in bone marrow-derived inflammatory cells attenuated pressure overload-induced hypertrophy and dysfunction. Mechanistically, MYDGF inhibited G protein-coupled receptor agonist-induced hypertrophy and augmented SERCA2a (sarco/endoplasmic reticulum Ca2+-ATPase 2a) expression in cultured neonatal rat ventricular cardiomyocytes by enhancing PIM1 (Pim-1 proto-oncogene, serine/threonine kinase) expression and activity. Along this line, cardiomyocytes from pressure-overloaded Mydgf-/- mice displayed reduced PIM1 and SERCA2a expression, greater hypertrophy, and impaired Ca2+ cycling and sarcomere function compared with cardiomyocytes from pressure-overloaded WT mice. Transplanting Mydgf-/- mice with WT bone marrow cells augmented cardiac PIM1 and SERCA2a levels and ameliorated pressure overload-induced hypertrophy and dysfunction. Pressure-overloaded Mydgf-/- mice were similarly rescued by adenoviral Serca2a gene transfer. Treating pressure-overloaded WT mice subcutaneously with recombinant MYDGF enhanced SERCA2a expression, attenuated left ventricular hypertrophy and dysfunction, and improved survival.These findings establish a MYDGF-based adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against pressure overload-induced heart failure.

    View details for DOI 10.1161/CIRCULATIONAHA.120.053365

    View details for PubMedID 34372689

  • Angiogenesis after acute myocardial infarction. Cardiovascular research Wu, X., Reboll, M. R., Korf-Klingebiel, M., Wollert, K. C. 2021; 117 (5): 1257-1273


    Acute myocardial infarction (MI) inflicts massive injury to the coronary microcirculation leading to vascular disintegration and capillary rarefication in the infarct region. Tissue repair after MI involves a robust angiogenic response that commences in the infarct border zone and extends into the necrotic infarct core. Technological advances in several areas have provided novel mechanistic understanding of postinfarction angiogenesis and how it may be targeted to improve heart function after MI. Cell lineage tracing studies indicate that new capillary structures arise by sprouting angiogenesis from pre-existing endothelial cells (ECs) in the infarct border zone with no meaningful contribution from non-EC sources. Single-cell RNA sequencing shows that ECs in infarcted hearts may be grouped into clusters with distinct gene expression signatures, likely reflecting functionally distinct cell populations. EC-specific multicolour lineage tracing reveals that EC subsets clonally expand after MI. Expanding EC clones may arise from tissue-resident ECs with stem cell characteristics that have been identified in multiple organs including the heart. Tissue repair after MI involves interactions among multiple cell types which occur, to a large extent, through secreted proteins and their cognate receptors. While we are only beginning to understand the full complexity of this intercellular communication, macrophage and fibroblast populations have emerged as major drivers of the angiogenic response after MI. Animal data support the view that the endogenous angiogenic response after MI can be boosted to reduce scarring and adverse left ventricular remodelling. The improved mechanistic understanding of infarct angiogenesis therefore creates multiple therapeutic opportunities. During preclinical development, all proangiogenic strategies should be tested in animal models that replicate both cardiovascular risk factor(s) and the pharmacotherapy typically prescribed to patients with acute MI. Considering that the majority of patients nowadays do well after MI, clinical translation will require careful selection of patients in need of proangiogenic therapies.

    View details for DOI 10.1093/cvr/cvaa287

    View details for PubMedID 33063086

  • Heparan Sulfate-Editing Extracellular Sulfatases Enhance VEGF Bioavailability for Ischemic Heart Repair. Circulation research Korf-Klingebiel, M., Reboll, M. R., Grote, K., Schleiner, H., Wang, Y., Wu, X., Klede, S., Mikhed, Y., Bauersachs, J., Klintschar, M., Rudat, C., Kispert, A., Niessen, H. W., Lübke, T., Dierks, T., Wollert, K. C. 2019; 125 (9): 787-801


    Mechanistic insight into the inflammatory response after acute myocardial infarction may inform new molecularly targeted treatment strategies to prevent chronic heart failure.We identified the sulfatase SULF2 in an in silico secretome analysis in bone marrow cells from patients with acute myocardial infarction and detected increased sulfatase activity in myocardial autopsy samples. SULF2 (Sulf2 in mice) and its isoform SULF1 (Sulf1) act as endosulfatases removing 6-O-sulfate groups from heparan sulfate (HS) in the extracellular space, thus eliminating docking sites for HS-binding proteins. We hypothesized that the Sulfs have a role in tissue repair after myocardial infarction.Both Sulfs were dynamically upregulated after coronary artery ligation in mice, attaining peak expression and activity levels during the first week after injury. Sulf2 was expressed by monocytes and macrophages, Sulf1 by endothelial cells and fibroblasts. Infarct border zone capillarization was impaired, scar size increased, and cardiac dysfunction more pronounced in mice with a genetic deletion of either Sulf1 or Sulf2. Studies in bone marrow-chimeric Sulf-deficient mice and Sulf-deficient cardiac endothelial cells established that inflammatory cell-derived Sulf2 and endothelial cell-autonomous Sulf1 promote angiogenesis. Mechanistically, both Sulfs reduced HS sulfation in the infarcted myocardium, thereby diminishing Vegfa (vascular endothelial growth factor A) interaction with HS. Along this line, both Sulfs rendered infarcted mouse heart explants responsive to the angiogenic effects of HS-binding Vegfa164 but did not modulate the angiogenic effects of non-HS-binding Vegfa120. Treating wild-type mice systemically with the small molecule HS-antagonist surfen (bis-2-methyl-4-amino-quinolyl-6-carbamide, 1 mg/kg/day) for 7 days after myocardial infarction released Vegfa from HS, enhanced infarct border-zone capillarization, and exerted sustained beneficial effects on cardiac function and survival.These findings establish HS-editing Sulfs as critical inducers of postinfarction angiogenesis and identify HS sulfation as a therapeutic target for ischemic tissue repair.

    View details for DOI 10.1161/CIRCRESAHA.119.315023

    View details for PubMedID 31434553

  • Effects of Mobile Text Messaging on Glycemic Control in Patients With Coronary Heart Disease and Diabetes Mellitus. Circulation. Cardiovascular quality and outcomes Huo, X., Krumholz, H. M., Bai, X., Spatz, E. S., Ding, Q., Horak, P., Zhao, W., Gong, Q., Zhang, H., Yan, X., Sun, Y., Liu, J., Wu, X., Guan, W., Wang, X., Li, J., Li, X., Spertus, J. A., Masoudi, F. A., Zheng, X. 2019; 12 (9): e005805


    BACKGROUND: Mobile health interventions may support risk factor management and are readily scalable in healthcare systems. We aim to evaluate the efficacy of a text messaging-based intervention to improve glycemic control in patients with coronary heart disease and diabetes mellitus in China.METHODS AND RESULTS: The CHAT-DM study (Cardiovascular Health and Texting-Diabetes Mellitus) was a parallel-group, single-blind, randomized clinical trial that included 502 patients with both coronary heart disease and diabetes mellitus from 34 hospitals in China. The intervention group (n=251) received 6 text messages per week for 6 months in addition to usual care. Messages were theory driven and culturally tailored to provide educational and motivational information on glucose monitoring, blood pressure control, medication adherence, physical activity, and lifestyle. The control group (n=251) received usual care and 2 thank you messages per month. The primary outcome was change in glycated hemoglobin (HbA1C [hemoglobin A1C]) from baseline to 6 months. Secondary outcomes were change in proportion of patients achieving HbA1C <7%, fasting blood glucose, systolic blood pressure, LDL (low-density lipoprotein) cholesterol, body mass index, and physical activity from baseline to 6 months. The end points were assessed using analyses of covariance. The follow-up rate was 99%. When compared with control group at 6 months, the intervention group had a greater reduction in HbA1C (-0.2% versus 0.1%; P=0.003) and a greater proportion of participants who achieved HbA1C <7% (69.3% versus 52.6%; P=0.004). Change in fasting blood glucose was larger in the intervention group (between-group difference: -0.6 mmol/L; 95% CI, -1.1 to -0.2; P=0.011), but no other outcome differences were observed. Nearly all participants reported that messages were easy to understand (97.1%) and useful (94.1%).CONCLUSIONS: A text message intervention resulted in better glycemic control in patients with diabetes mellitus and coronary heart disease. While the mechanism of this benefit remains to be determined, the results suggest that a simple, culturally sensitive mobile text messaging program may provide an effective and feasible way to improve disease self-management.CLINICAL TRIAL REGISTRATION: URL: Unique identifier: NCT02883842.

    View details for DOI 10.1161/CIRCOUTCOMES.119.005805

    View details for PubMedID 31474119

  • Effect of Text Messaging on Risk Factor Management in Patients With Coronary Heart Disease The CHAT Randomized Clinical Trial CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Zheng, X., Spatz, E. S., Bai, X., Huo, X., Ding, Q., Horak, P., Wu, X., Guan, W., Chow, C. K., Yan, X., Sun, Y., Wang, X., Zhang, H., Liu, J., Li, J., Li, X., Spertus, J. A., Masoudi, F. A., Krumholz, H. M. 2019; 12 (4)
  • Effect of Text Messaging on Risk Factor Management in Patients With Coronary Heart Disease. Circulation. Cardiovascular quality and outcomes Zheng, X. n., Spatz, E. S., Bai, X. n., Huo, X. n., Ding, Q. n., Horak, P. n., Wu, X. n., Guan, W. n., Chow, C. K., Yan, X. n., Sun, Y. n., Wang, X. n., Zhang, H. n., Liu, J. n., Li, J. n., Li, X. n., Spertus, J. A., Masoudi, F. A., Krumholz, H. M. 2019; 12 (4): e005616


    Mobile health technologies are low cost, scalable interventions with the potential to promote patient engagement and behavior change. We aimed to test whether a culturally sensitive text messaging intervention supporting secondary prevention improves the control of risk factors in patients with coronary heart disease in China.In this multicenter, single-blinded randomized controlled trial, 822 patients (mean age, 56.4 [SD, 9.5] years; 14.1% women) with coronary heart disease and without diabetes mellitus from 37 hospitals in China were enrolled between August 2016 and March 2017. In addition to usual care, the control group (n=411) received 2 thank you messages/month; the intervention group (n=411) received 6 text messages/week for 6 months delivered by an automated computerized system. The messages provided educational and motivational information related to disease-specific knowledge, risk factor control, physical activity, and medication adherence. The primary end point was change in systolic blood pressure from baseline to 6 months. Secondary end points included the proportion with systolic blood pressure <140 mm Hg, smoking status, and change in body mass index, LDL-C (low-density lipoprotein cholesterol), and physical activity (assessed using the International Physical Activity Questionnaire). The end points were assessed using analyses of covariance. Follow-up was 99.6%. At 6 months, systolic blood pressure was not significantly lower in the intervention group compared with the control group, with a mean change (SD) of 3.2 (14.3) mm Hg and 2.0 (15.0) mm Hg ( P>0.05) from baseline, respectively (mean net change, -1.3 mm Hg [95% CI, -3.3 to 0.8]; P=0.221). There were no significant differences in the change in LDL-C level, physical activity, body mass index, or smoking status between the 2 groups. Nearly all patients in the intervention group reported the text messages to be useful (96.1%), easy to understand (98.8%), appropriate in frequency (93.8%), and reported being willing to receive future text messages (94.8%).Text messages supporting secondary prevention among patients with coronary heart disease did not lead to a greater reduction in blood pressure at 6 months. Mobile phone text messaging for secondary prevention was feasible and highly acceptable to patients.URL: . Unique identifier: NCT02888769.

    View details for PubMedID 30998400

  • Traditional Chinese Medicine for Acute Myocardial Infarction in Western Medicine Hospitals in China. Circulation. Cardiovascular quality and outcomes Spatz, E. S., Wang, Y., Beckman, A. L., Wu, X., Lu, Y., Du, X., Li, J., Xu, X., Davidson, P. M., Masoudi, F. A., Spertus, J. A., Krumholz, H. M., Jiang, L. 2018; 11 (3): e004190


    Amid national efforts to improve the quality of care for people with cardiovascular disease in China, the use of traditional Chinese medicine (TCM) is increasing, yet little is known about its use in the early management of acute myocardial infarction (AMI).We aimed to examine intravenous use of TCM within the first 24 hours of hospitalization (early IV TCM) for AMI. Data come from the China Patient-centered Evaluative Assessment of Cardiac Events Retrospective Study of Acute Myocardial Infarction, restricted to a large, representative sample of Western medicine hospitals throughout China (n=162). We conducted a chart review of randomly sampled patients with AMI in 2001, 2006, and 2011, comparing early intravenous TCM use across years, predictors of any early intravenous TCM use, and association with in-hospital bleeding and mortality. From 2001 to 2011, early intravenous TCM use increased (2001: 38.2% versus 2006: 49.1% versus 2011: 56.1%; P<0.01). Nearly all (99%) hospitals used early intravenous TCM. Salvia miltiorrhiza was most commonly prescribed, used in one third (35.5%) of all patients admitted with AMI. Patients receiving any early intravenous TCM, compared with those who did not, were similar in age and sex and had fewer cardiovascular risk factors. In multivariable hierarchical models, admission to a secondary (versus tertiary) hospital was most strongly associated with early intravenous TCM use (odds ratio: 2.85; 95% confidence interval: 1.98-4.11). Hospital-level factors accounted for 55% of the variance (adjusted median odds ratio: 2.84). In exploratory analyses, there were no significant associations between early intravenous TCM and in-hospital bleeding or mortality.Early intravenous TCM use for AMI in China is increasing despite the lack of evidence of their benefit or harm. There is an urgent need to define the effects of these medications because they have become a staple of treatment in the world's most populous country.URL: Unique identifier: NCT01624883.

    View details for DOI 10.1161/CIRCOUTCOMES.117.004190

    View details for PubMedID 29848478

    View details for PubMedCentralID PMC5882246