Han Zhu

All Publications

• Classes of Antineoplastic Agents Associated with Increased Risk of Cancer Therapy-associated Hypertension and Management Strategies. Cardiology clinics Sayegh, H., Zagouras, A., Neal, J. W., Witteles, R. M., Zhu, H., Waliany, S. 2025; 43 (1): 31-42

  Abstract

  Hypertension (HTN) has been found to be the most common comorbidity in patients with cancer. In addition to increased prevalence of baseline HTN, patients with cancer may be at increased risk of HTN as a short-term or long-term adverse event from cancer therapy. Different classes of cancer therapies have been implicated in the development of HTN, including inhibitors of vascular endothelial growth factor (VEGF), Bruton tyrosine kinase inhibitors, proteasome inhibitors, androgen deprivation therapy, and others. While some of these drugs may lead to increases in blood pressure through on-target effects (eg, with VEGF inhibition), others may be associated with HTN from off-target mechanisms that are not always well understood.

  View details for DOI 10.1016/j.ccl.2024.08.006

  View details for PubMedID 39551560

• Predictors and Risk Score for Immune Checkpoint-Inhibitor-Associated Myocarditis Severity. medRxiv : the preprint server for health sciences Power, J. R., Dolladille, C., Ozbay, B., Procureur, A. M., Ederhy, S., Palaskas, N. L., Lehmann, L. H., Cautela, J., Courand, P. Y., Hayek, S. S., Zhu, H., Zaha, V. G., Cheng, R. K., Alexandre, J., Roubille, F., Baldassarre, L. A., Chen, Y. C., Baik, A. H., Laufer-Perl, M., Tamura, Y., Asnani, A., Francis, S., Gaughan, E. M., Rainer, P. P., Bailly, G., Flint, D., Arangalage, D., Cariou, E., Florido, R., Narezkina, A., Liu, Y., Sandhu, S., Leong, D., Issa, N., Piriou, N., Heinzerling, L., Peretto, G., Crusz, S. M., Akhter, N., Levenson, J. E., Turker, I., Eslami, A., Fenioux, C., Moliner, P., Obeid, M., Chan, W. T., Ewer, S. M., Kassaian, S. E., Johnson, D. B., Nohria, A., Zadok, O. I., Moslehi, J. J., Salem, J. E. 2024

  Abstract

  Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking.A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [95%confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated.In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score≥4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events.ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well.NCT04294771 and NCT05454527.

  View details for DOI 10.1101/2024.06.02.24308336

  View details for PubMedID 38883792

  View details for PubMedCentralID PMC11177901

• Immune checkpoints in cardiac physiology and pathology: therapeutic targets for heart failure. Nature reviews. Cardiology Gergely, T. G., Drobni, Z. D., Kallikourdis, M., Zhu, H., Meijers, W. C., Neilan, T. G., Rassaf, T., Ferdinandy, P., Varga, Z. V. 2024

  Abstract

  Immune checkpoint molecules are physiological regulators of the adaptive immune response. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies targeting programmed cell death protein 1 or cytotoxic T lymphocyte-associated protein 4, have revolutionized cancer treatment and their clinical use is increasing. However, ICIs can cause various immune-related adverse events, including acute and chronic cardiotoxicity. Of these cardiovascular complications, ICI-induced acute fulminant myocarditis is the most studied, although emerging clinical and preclinical data are uncovering the importance of other ICI-related chronic cardiovascular complications, such as accelerated atherosclerosis and non-myocarditis-related heart failure. These complications could be more difficult to diagnose, given that they might only be present alongside other comorbidities. The occurrence of these complications suggests a potential role of immune checkpoint molecules in maintaining cardiovascular homeostasis, and disruption of physiological immune checkpoint signalling might thus lead to cardiac pathologies, including heart failure. Although inflammation is a long-known contributor to the development of heart failure, the therapeutic targeting of pro-inflammatory pathways has not been successful thus far. The increasingly recognized role of immune checkpoint molecules in the failing heart highlights their potential use as immunotherapeutic targets for heart failure. In this Review, we summarize the available data on ICI-induced cardiac dysfunction and heart failure, and discuss how immune checkpoint signalling is altered in the failing heart. Furthermore, we describe how pharmacological targeting of immune checkpoints could be used to treat heart failure.

  View details for DOI 10.1038/s41569-023-00986-9

  View details for PubMedID 38279046

  View details for PubMedCentralID 5247797

• Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis (vol 29, pg 3100, 2023) NATURE MEDICINE Fenioux, C., Abbar, B., Boussouar, S., Bretagne, M., Power, J. R., Moslehi, J. J., Gougis, P., Amelin, D., Dechartres, A., Lehmann, L. H., Courand, P., Cautela, J., Alexandre, J., Procureur, A., Rozes, A., Leonard-Louis, S., Qin, J., Akhter, N., Aghel, N., Amidi, K., Anderson, E., Arangalage, D., Aras, M., Asnani, A., Baldassarre, L. A., Barovila, R., Barroso, A., Bottinor, W., Bouali, A., Cariou, E., Chang, W., Cheng, R. K., Crusz, S. M., Deswal, A., Dietrich, P., Dy, G., Docq, C., Ewer, S., Fernando, S., Flint, D. L., Florido, R., Fukushima, S., Galli, E., Gaughan, E., Habib, M., Haydon, A., Heinzerling, L., Ben Zadok, O., Issa, N., Karlstaedt, A., Kitagawa, K., Layoun, M., Laufer-Perl, M., Lenneman, C., Leong, D., Lesiuk, C., Levenson, J., Lopez-Fernandez, T., Liu, Y., Machado, K., Moliner, P., Morimoto, R., Obeid, M., Narezkina, A., Palaskas, N., Peretto, G., Piriou, N., Plana, J., Rainer, P. P., Robert-Halabi, M., Rocher, F., Rota, E., Roubille, F., Ruf, T., Sandhu, S., Sanjeev, F., Seki, N., Tajiri, K., Tamura, Y., Thuny, F., Tresorier, R., Turker, I., Warner, E., Zaha, V., Zhu, H., Cheynier, R., Charmeteau-De Muylder, B., Redheuil, A., Tubach, F., Cadranel, J., Milon, A., Ederhy, S., Similowski, T., Johnson, D. B., Pizzo, I., Catalan, T., Benveniste, O., Hayek, S. S., Allenbach, Y., Rosenzwajg, M., Dolladille, C., Salem, J. 2024

  View details for DOI 10.1038/s41591-023-02771-0

  View details for Web of Science ID 001135848400003

  View details for PubMedID 38172633

• A Novel Therapeutic Approach using CXCR3 Blockade to Treat Immune Checkpoint Inhibitor-mediated Myocarditis bioRxiv Huang, Y. V., Lee, D., Sun, Y., Chou, H., Xu, B., Lin, Z., Branche, C., Bayer, A. L., Waliany, S., Neal, J., Wakelee, H., Witteles, R. M., Nguyen, P., Graves, E. E., Alcaide, P., Berry, G. J., Wu, S. M., Zhu, H. 2024

  View details for DOI 10.1101/2024.01.30.576279

• THE IMPACT OF ROUTINE CARDIAC TROPONIN I-BASED CARDIOTOXICITY SCREENING ON CLINICAL OUTCOMES IN PATIENTS ON CANCER IMMUNOTHERAPY biorxv Ivanovic, M., Chan, A., Cheng, E., Xu, S., Lee, C., Franquiz, M., You, J., Fazal, M., Batchelder, R., Reddy, S., Katsumoto, T., Ramchandran, K., Colevas, A., Khan, S., Fan, A., Cheng, P., Wakelee, H., Wu, S. M., Witteles, R. M., Neal, J. W., Waliany, S., Zhu, H. 2024

  View details for DOI 10.1101/2024.01.22.24301442

• Immunotherapy-Associated Atherosclerosis: A Comprehensive Review of Recent Findings and Implications for Future Research. Current treatment options in cardiovascular medicine Chan, A., Torelli, S., Cheng, E., Batchelder, R., Waliany, S., Neal, J., Witteles, R., Nguyen, P., Cheng, P., Zhu, H. 2023; 25 (12): 715-735

  Abstract

  Even as immune checkpoint inhibitors (ICIs) have transformed the lifespan of many patients, they may also trigger acceleration of long-term cardiovascular disease. Our review aims to examine the current landscape of research on ICI-mediated atherosclerosis and address key questions regarding its pathogenesis and impact on patient management.Preclinical mouse models suggest that T cell dysregulation and proatherogenic cytokine production are key contributors to plaque development after checkpoint inhibition. Clinical data also highlight the significant burden of atherosclerotic cardiovascular disease (ASCVD) in patients on immunotherapy, although the value of proactively preventing and treating ASCVD in this population remains an open area of inquiry. Current treatment options include dietary/lifestyle modification and traditional medications to manage hypertension, hyperlipidemia, and diabetes risk factors; no current targeted therapies exist.Early identification of high-risk patients is crucial for effective preventive strategies and timely intervention. Future research should focus on refining screening tools, elucidating targetable mechanisms driving ICI atherosclerosis, and evaluating long-term cardiovascular outcomes in cancer survivors who received immunotherapy. Moreover, close collaboration between oncologists and cardiologists is essential to optimize patient outcomes.

  View details for DOI 10.1007/s11936-023-01024-0

  View details for PubMedID 38213548

  View details for PubMedCentralID PMC10776491

• miR-222 inhibits pathological cardiac hypertrophyand heart failure. Cardiovascular research Liu, X., Li, H., Hastings, M. H., Xiao, C., Damilano, F., Platt, C., Lerchenmüller, C., Zhu, H., Wei, X. P., Yeri, A., Most, P., Rosenzweig, A. 2023

  Abstract

  Physiological cardiac hypertrophy occurs in response to exercise and can protect against pathological stress. In contrast, pathological hypertrophy occurs in disease and often precedes heart failure. The cardiac pathways activated in physiological and pathological hypertrophy are largely distinct. Our prior work demonstrated that miR-222 increases in exercised hearts and is required for exercise-induced cardiac hypertrophy and cardiomyogenesis. Here, we sought to define the role of miR-222 in pathological hypertrophy.We found that miR-222 also increased in pathological hypertrophy induced by pressure overload. To assess its functional significance in this setting, we generated a miR-222 gain-of-function model through cardiac-specific constitutive transgenic miR-222 expression (TgC-miR-222) and used locked nucleic acid (LNA) anti-miR specific for miR-222 to inhibit its effects. Both gain- and loss-of-function models manifested normal cardiac structure and function at baseline. However, after transverse aortic constriction (TAC), miR-222 inhibition accelerated the development of pathological hypertrophy, cardiac dysfunction, and heart failure. Conversely, miR-222-overexpressing mice had less pathological hypertrophy after TAC, as well as better cardiac function and survival. We identified PUMA, a pro-apoptotic Bcl-2 family member, and the transcription factors, Hmbox1 and NFATc3, as direct miR-222 targets contributing to its roles in this context.While miR-222 is necessary for physiological cardiac growth, it inhibits cardiac growth in response to pressure overload and reduces adverse remodeling and cardiac dysfunction. These findings support the model that physiological and pathological hypertrophy are fundamentally different. Further, they suggest miR-222 may hold promise as a therapeutic target in pathological cardiac hypertrophy and heart failure.We report that miR-222 was necessary and sufficient to limit cardiac growth, cardiomyocyte cell death, adverse ventricular remodeling, and cardiac dysfunction in response to pressure overload. This suggests possible therapeutic value, particularly as miR-222 is conserved between mice and humans and regulated by exercise in both.

  View details for DOI 10.1093/cvr/cvad184

  View details for PubMedID 38084908

• Osimertinib-Associated Cardiomyopathy In Patients With Non-Small Cell Lung Cancer: A Case Series JACC: CardioOncology Franquiz, M., Waliany, S., Xu, A., Hnatiuk, A., Wu, S., Cheng, P., Wakelee, H., Neal, J., Witteles, R., Zhu, H. 2023: 839-841

  View details for DOI 10.1016/j.jaccao.2023.07.006

  View details for PubMedCentralID PMC10774774

• Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis. Circulation Lehmann, L. H., Heckmann, M. B., Bailly, G., Finke, D., Procureur, A., Power, J. R., Stein, F., Bretagne, M., Ederhy, S., Fenioux, C., Hamwy, O., Funck-Brentano, E., Romano, E., Pieroni, L., Münster, J., Allenbach, Y., Anquetil, C., Leonard-Louis, S., Palaskas, N. L., Hayek, S. S., Katus, H. A., Giannitsis, E., Frey, N., Kaya, Z., Moslehi, J., Prifti, E., Salem, J. E. 2023

  Abstract

  Immune checkpoint inhibitors (ICIs) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, specifically troponin-I (cTnI), troponin-T (cTnT), and creatine kinase (CK), are used for diagnosis. However, the association between temporal elevations of these biomarkers with disease trajectory and outcomes has not been established.We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT, and CK in patients with ICI myocarditis (n=60) through 1-year follow-up in 2 cardio-oncology units (APHP Sorbonne: Paris, France and Heidelberg, Germany). A total of 1751 (1 cTnT assay type), 920 (4 cTnI assay types), and 1191 CK sampling time points were available. Major adverse cardiomyotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular or sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and sudden cardiac death. Diagnostic performance of cTnI and cTnT was also assessed in an international ICI myocarditis registry.Within 72 hours of admission, cTnT, cTnI, and CK were increased compared with upper reference limits (URLs) in 56 of 57 (98%), 37 of 42 ([88%] P=0.03 versus cTnT), and 43 of 57 ([75%] P<0.001 versus cTnT), respectively. This increased rate of positivity for cTnT (93%) versus cTnI ([64%] P<0.001) on admission was confirmed in 87 independent cases from an international registry comprising 13 countries. In the Franco-German cohort, 24 of 60 (40%) patients developed ≥1 MACE (total, 52; median time to first MACE, 5 [interquartile range, 2-16] days). The highest value of cTnT:URL within the first 72 hours of admission performed best in terms of association with MACE within 90 days (area under the curve, 0.84) than CK:URL (area under the curve, 0.70). A cTnT:URL ≥32 within 72 hours of admission was the best cut-off associated with MACE within 90 days (hazard ratio, 11.1 [95% CI, 3.2-38.0]; P<0.001), after adjustment for age and sex. cTnT was increased in all patients within 72 hours of the first MACE (23 of 23 [100%]), whereas cTnI and CK values were less than the URL in 2 of 19 (11%) and 6 of 22 (27%) of patients (P<0.001), respectively.cTnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis. A cTnT:URL ratio <32 within 72 hours of diagnosis is associated with a subgroup at low risk for MACE. Potential differences in diagnostic and prognostic performances between cTnT and cTnI as a function of the assays used deserve further evaluation in ICI myocarditis.

  View details for DOI 10.1161/CIRCULATIONAHA.123.062405

  View details for PubMedID 37317858

• Pharmacovigilance Analysis of HeartFailure Associated With Anti-HER2 Monotherapies and Combination Regimens for Cancer. JACC. CardioOncology Waliany, S., Caswell-Jin, J., Riaz, F., Myall, N., Zhu, H., Witteles, R. M., Neal, J. W. 2023; 5 (1): 85-98

  Abstract

  Background: Trastuzumab improves outcomes in patients with HER2-overexpressing malignancies but is associated with decreases in left ventricular ejection fraction. Heart failure (HF) risks from other anti-HER2 therapies are less clear.Objectives: Using World Health Organization pharmacovigilance data, the authors compared HF odds across anti-HER2 regimens.Methods: In VigiBase, 41,976 patients had adverse drug reactions (ADRs) with anti-HER2 monoclonal antibodies (trastuzumab, n=16,900; pertuzumab, n=1,856), antibody-drug conjugates (trastuzumab emtansine [T-DM1], n=3,983; trastuzumab deruxtecan, n=947), and tyrosine kinase inhibitors (afatinib, n=10,424; lapatinib, n=5,704; neratinib, n=1,507; tucatinib, n=655); additionally, 36,052 patients had ADRs with anti-HER2-based combination regimens. Most patients had breast cancer (monotherapies, n=17,281; combinations, n=24,095). Outcomes included comparison of HF odds with each monotherapy relative to trastuzumab, within each therapeutic class, and among combination regimens.Results: Of 16,900 patients with trastuzumab-associated ADRs, 2,034 (12.04%) had HF reports (median time to onset 5.67months; IQR: 2.85-9.32months) compared with 1% to 2% with antibody-drug conjugates. Trastuzumab had higher odds of HF reporting relative to other anti-HER2 therapies collectively in the overall cohort (reporting OR [ROR]: 17.37; 99% CI: 14.30-21.10) and breast cancer subgroup (ROR: 17.10; 99% CI: 13.12-22.27). Pertuzumab/T-DM1 had 3.4 times higher odds of HF reporting than T-DM1 monotherapy; tucatinib/trastuzumab/capecitabine had similar odds as tucatinib. Among metastatic breast cancer regimens, HF odds were highest with trastuzumab/pertuzumab/docetaxel (ROR: 1.42; 99% CI: 1.17-1.72) and lowest with lapatinib/capecitabine (ROR: 0.09; 99% CI: 0.04-0.23).Conclusions: Trastuzumab and pertuzumab/T-DM1 had higher odds of HF reporting than other anti-HER2 therapies. These data provide large-scale, real-world insight into which HER2-targeted regimens would benefit from left ventricular ejection fraction monitoring.

  View details for DOI 10.1016/j.jaccao.2022.09.007

  View details for PubMedID 36875913

• The potential of auto-antigen-guided treatment of immune checkpoint inhibitor-mediated myocarditis. Med (New York, N.Y.) Zhu, H., Huang, Y. V., Wu, S. M. 2023; 4 (1): 13-14

  Abstract

  Immune checkpoint inhibitor (ICI)-mediated myocarditis is a rare but devastating side effect of cancer immunotherapy with up to 40% mortality and long-term cardiac issues such as arrhythmias and heart failure in affected patients.1 Recently, Axelrod et al.2 suggested an auto-antigen-driven mechanism as the immunological basis for this disease.

  View details for DOI 10.1016/j.medj.2022.12.005

  View details for PubMedID 36640753

• Late-Onset Immunotherapy-Induced Myocarditis 2 Years After Checkpoint Inhibitor Initiation. JACC. CardioOncology Nguyen, A. T., Berry, G. J., Witteles, R. M., Le, D. T., Wu, S. M., Fisher, G. A., Zhu, H. 2022; 4 (5): 727-730

  View details for DOI 10.1016/j.jaccao.2022.04.007

  View details for PubMedID 36636432

  View details for PubMedCentralID PMC9830192

• The Role of Single-Cell Profiling and Deep Immunophenotyping in Understanding Immune Therapy Cardiotoxicity. JACC. CardioOncology Huang, Y. V., Waliany, S., Lee, D., Galdos, F. X., Witteles, R. M., Neal, J. W., Fan, A. C., Maecker, H. T., Nguyen, P. K., Wu, S. M., Zhu, H. 2022; 4 (5): 629-634

  Abstract

  • ICIs used in cancer therapy can cause serious cardiac immune-related side effects. • Single-cell multi-omics are powerful tools in understanding cell subsets/phenotypes. • Multi-omics technology can elucidate disease mechanisms in ICI-induced myocarditis.

  View details for DOI 10.1016/j.jaccao.2022.08.012

  View details for PubMedID 36636436

  View details for PubMedCentralID PMC9830194

• devCellPy is a machine learning-enabled pipeline for automated annotation of complex multilayered single-cell transcriptomic data. Nature communications Galdos, F. X., Xu, S., Goodyer, W. R., Duan, L., Huang, Y. V., Lee, S., Zhu, H., Lee, C., Wei, N., Lee, D., Wu, S. M. 2022; 13 (1): 5271

  Abstract

  A major informatic challenge in single cell RNA-sequencing analysis is the precise annotation of datasets where cells exhibit complex multilayered identities or transitory states. Here, we present devCellPy a highly accurate and precise machine learning-enabled tool that enables automated prediction of cell types across complex annotation hierarchies. To demonstrate the power of devCellPy, we construct a murine cardiac developmental atlas from published datasets encompassing 104,199 cells from E6.5-E16.5 and train devCellPy to generate a cardiac prediction algorithm. Using this algorithm, we observe a high prediction accuracy (>90%) across multiple layers of annotation and across de novo murine developmental data. Furthermore, we conduct a cross-species prediction of cardiomyocyte subtypes from in vitro-derived human induced pluripotent stem cells and unexpectedly uncover a predominance of left ventricular (LV) identity that we confirmed by an LV-specific TBX5 lineage tracing system. Together, our results show devCellPy to be a useful tool for automated cell prediction across complex cellular hierarchies, species, and experimental systems.

  View details for DOI 10.1038/s41467-022-33045-x

  View details for PubMedID 36071107

• Identification of Pathogenic Immune Cell Subsets Associated With Checkpoint Inhibitor-Induced Myocarditis. Circulation Zhu, H., Galdos, F. X., Lee, D., Waliany, S., Vivian Huang, Y., Ryan, J., Dang, K., Neal, J. W., Wakelee, H. A., Reddy, S. A., Srinivas, S., Lin, L. L., Witteles, R. M., Maecker, H. T., Davis, M. M., Nguyen, P. K., Wu, S. M. 2022: 101161CIRCULATIONAHA121056730

  Abstract

  Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune-related adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T cell-mediated mechanisms. However, the precise pathological immune subsets and molecular changes in ICI myocarditis are unknown.To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry on peripheral blood mononuclear cells from 52 individuals: 29 patients with autoimmune adverse events (immune-related adverse events) on ICI, including 8 patients with ICI myocarditis, and 23 healthy control subjects. We also used multiomics single-cell technology to immunophenotype 30 patients/control subjects using single-cell RNA sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes by sequencing with feature barcoding for surface marker expression confirmation. To correlate between the blood and the heart, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing on MRL/Pdcd1-/- (Murphy Roths large/programmed death-1-deficient) mice with spontaneous myocarditis.Using these complementary approaches, we found an expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in patients with ICI myocarditis compared with control subjects. T-cell receptor sequencing demonstrated that these CD8+ Temra cells were clonally expanded in patients with myocarditis compared with control subjects. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype 2 months after treatment with glucocorticoids. Differential expression analysis demonstrated elevated expression levels of proinflammatory chemokines (CCL5/CCL4/CCL4L2) in the clonally expanded Temra CD8+ cells, and ligand receptor analysis demonstrated their interactions with innate immune cells, including monocytes/macrophages, dendritic cells, and neutrophils, as well as the absence of key anti-inflammatory signals. To complement the human study, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing in Pdcd1-/- mice with spontaneous myocarditis and found analogous expansions of cytotoxic clonal effector CD8+ cells in both blood and hearts of such mice compared with controls.Clonal cytotoxic Temra CD8+ cells are significantly increased in the blood of patients with ICI myocarditis, corresponding to an analogous increase in effector cytotoxic CD8+ cells in the blood/hearts of Pdcd1-/- mice with myocarditis. These expanded effector CD8+ cells have unique transcriptional changes, including upregulation of chemokines CCL5/CCL4/CCL4L2, which may serve as attractive diagnostic/therapeutic targets for reducing life-threatening cardiac immune-related adverse events in ICI-treated patients with cancer.

  View details for DOI 10.1161/CIRCULATIONAHA.121.056730

  View details for PubMedID 35762356

• Pharmacovigilance analysis of cardiac toxicities associated with targeted therapies for metastatic non-small cell lung carcinoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Waliany, S., Zhu, H., Wakelee, H., Padda, S. K., Das, M., Ramchandran, K., Myall, N. J., Chen, T., Witteles, R. M., Neal, J. W. 2021

  Abstract

  INTRODUCTION: Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung carcinoma (NSCLC). We compared cardiovascular adverse events between and within targeted therapy classes.METHODS: We used WHO pharmacovigilance database VigiBase to compare odds of heart failure, conduction disease, QT prolongation, supraventricular tachycardia (SVT), and ventricular arrhythmias between inhibitors of EGFR (erlotinib, gefitinib, afatinib, osimertinib), BRAF (dabrafenib), MEK (trametinib), and ALK ± ROS1 (alectinib, brigatinib, ceritinib, crizotinib, lorlatinib).RESULTS: Of 98,765 adverse reactions reported with NSCLC targeted therapies, 1,783 (1.8%) were arrhythmias and 1,146 (1.2%) were heart failure. ALK/ROS1 inhibitors were associated with increased odds of conduction disease (reporting odds ratio [ROR] 12.95, 99% CI: 10.14-16.55) and QT prolongation (ROR 5.16, 99% CI: 3.92-6.81) relative to BRAF and EGFR inhibitors. Among ALK/ROS1 inhibitors, crizotinib had highest odds of conduction disease (ROR 1.75, 99% CI: 1.30-2.36) and QT prolongation (ROR 1.91, 99% CI: 1.22-3.00). Dabrafenib (ROR 2.24, 99% CI: 1.86-2.70) and trametinib (ROR 2.44, 99% CI: 2.03-2.92) had higher odds of heart failure than other targeted therapies. Osimertinib was strongly associated with QT prolongation (ROR 6.13, 99% CI: 4.43-8.48), heart failure (ROR 3.64, 99% CI: 2.94-4.50), and SVT (ROR 1.90, 99% CI: 1.26-2.86) relative to other targeted therapies.CONCLUSIONS: ALK/ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than other targeted therapies. Osimertinib is strongly associated with QT prolongation, SVT, and heart failure relative to other EGFR inhibitors and targeted therapies. Monitoring for heart failure and arrhythmias should be considered with NSCLC targeted therapies, especially osimertinib.

  View details for DOI 10.1016/j.jtho.2021.07.030

  View details for PubMedID 34418561

• Myocarditis Surveillance with High-Sensitivity Troponin I During Cancer Treatment with Immune Checkpoint Inhibitors. JACC. CardioOncology Waliany, S., Neal, J. W., Reddy, S., Wakelee, H., Shah, S. A., Srinivas, S., Padda, S. K., Fan, A. C., Colevas, A. D., Wu, S. M., Witteles, R. M., Zhu, H. 2021; 3 (1): 137–39

  View details for DOI 10.1016/j.jaccao.2021.01.004

  View details for PubMedID 33796869

• Preclinical Models of Cancer Therapy-Associated Cardiovascular Toxicity: A Scientific Statement From the American Heart Association. Circulation research Asnani, A. n., Moslehi, J. J., Adhikari, B. B., Baik, A. H., Beyer, A. M., de Boer, R. A., Ghigo, A. n., Grumbach, I. M., Jain, S. n., Zhu, H. n. 2021: RES0000000000000473

  Abstract

  Although cardiovascular toxicity from traditional chemotherapies has been well recognized for decades, the recent explosion of effective novel targeted cancer therapies with cardiovascular sequelae has driven the emergence of cardio-oncology as a new clinical and research field. Cardiovascular toxicity associated with cancer therapy can manifest as a broad range of potentially life-threatening complications, including heart failure, arrhythmia, myocarditis, and vascular events. Beyond toxicology, the intersection of cancer and heart disease has blossomed to include discovery of genetic and environmental risk factors that predispose to both. There is a pressing need to understand the underlying molecular mechanisms of cardiovascular toxicity to improve outcomes in patients with cancer. Preclinical cardiovascular models, ranging from cellular assays to large animals, serve as the foundation for mechanistic studies, with the ultimate goal of identifying biologically sound biomarkers and cardioprotective therapies that allow the optimal use of cancer treatments while minimizing toxicities. Given that novel cancer therapies target specific pathways integral to normal cardiovascular homeostasis, a better mechanistic understanding of toxicity may provide insights into fundamental pathways that lead to cardiovascular disease when dysregulated. The goal of this scientific statement is to summarize the strengths and weaknesses of preclinical models of cancer therapy-associated cardiovascular toxicity, to highlight overlapping mechanisms driving cancer and cardiovascular disease, and to discuss opportunities to leverage cardio-oncology models to address important mechanistic questions relevant to all patients with cardiovascular disease, including those with and without cancer.

  View details for DOI 10.1161/RES.0000000000000473

  View details for PubMedID 33934611

• Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response Curr Cardiol Rep Zhu, H., Rhee, J., Cheng, P., Waliany, S., Chang, A., Witteles, R. M., Maecker, H., Davis, M. M., Nguyen, P. K., Wu, S. M. 2020; 22 (5)

  View details for DOI 10.1007/s11886-020-01292-3

• miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell metabolism Liu, X., Xiao, J., Zhu, H., Wei, X., Platt, C., Damilano, F., Xiao, C., Bezzerides, V., Boström, P., Che, L., Zhang, C., Spiegelman, B. M., Rosenzweig, A. 2015; 21 (4): 584-95

  Abstract

  Exercise induces physiological cardiac growth and protects the heart against pathological remodeling. Recent work suggests exercise also enhances the heart's capacity for repair, which could be important for regenerative therapies. While microRNAs are important in certain cardiac pathologies, less is known about their functional roles in exercise-induced cardiac phenotypes. We profiled cardiac microRNA expression in two distinct models of exercise and found microRNA-222 (miR-222) was upregulated in both. Downstream miR-222 targets modulating cardiomyocyte phenotypes were identified, including HIPK1 and HMBOX1. Inhibition of miR-222 in vivo completely blocked cardiac and cardiomyocyte growth in response to exercise while reducing markers of cardiomyocyte proliferation. Importantly, mice with inducible cardiomyocyte miR-222 expression were resistant to adverse cardiac remodeling and dysfunction after ischemic injury. These studies implicate miR-222 as necessary for exercise-induced cardiomyocyte growth and proliferation in the adult mammalian heart and show that it is sufficient to protect the heart against adverse remodeling.

  View details for DOI 10.1016/j.cmet.2015.02.014

  View details for PubMedID 25863248

  View details for PubMedCentralID PMC4393846

• Impact of Troponin Monitoring on Cardiac Outcomes in Patients Receiving Immune Checkpoint Inhibitors Ivanovic, M., Chan, A., Franquiz, M., Xu, S., Lee, C., Fazal, M., You, J., Witteles, R., Neal, J., Wu, S., Waliany, S., Zhu, H. WILEY. 2023: 2087-2089

  View details for Web of Science ID 001190014302060

• OSIMERTINIB-ASSOCIATED CARDIOMYOPATHY: A RETROSPECTIVE ANALYSIS OF THE STANFORD NON-SMALL CELL LUNG CANCER PATIENT COHORT Franquiz, M., Witteles, R., Zhu, H., Waliany, S. ELSEVIER SCIENCE INC. 2023: 411

  View details for Web of Science ID 000990866100412

• ACUTE CARDIOMYOPATHY AFTER INITIATION OF CABOZANTINIB, A MULTITYROSINE KINASE INHIBITOR Cheng, E., Zhu, H. ELSEVIER SCIENCE INC. 2023: 2670

  View details for Web of Science ID 000990866102681

• Immunotherapy-Associated Atherosclerosis: A Comprehensive Review of Recent Findings and Implications for Future Research Current Treatment Options in Cardiovascular Medicine Chan, A., Torelli, S., Cheng, E., Batchelder, R., Waliany, S., Neal, J., Witteles, R., Nguyen, P., Cheng, P., Zhu, H. 2023

  View details for DOI 10.1007/s11936-023-01024-0

• Pharmacovigilance Analysis of Heart Failure Associated With Anti-HER2 Monotherapies and Combination Regimens for Cancer Jacc: CardioOncology Waliany, S., Caswell-Jin, J., Riaz, F., Myall, N., Zhu, H., Witteles, R. M., Neal, J. W. 2023; 5 (1): 85-98
• Coronary artery disease and revascularization associated with immune checkpoint blocker myocarditis: Report from an international registry. European journal of cancer (Oxford, England : 1990) Nowatzke, J., Guedeney, P., Palaskas, N., Lehmann, L., Ederhy, S., Zhu, H., Cautela, J., Francis, S., Courand, P. Y., Deswal, A., Ewer, S. M., Aras, M., Arangalage, D., Ghafourian, K., Fenioux, C., Finke, D., Peretto, G., Zaha, V., Itzhaki Ben Zadok, O., Tajiri, K., Akhter, N., Levenson, J., Baldassarre, L., Power, J., Huang, S., Collet, J. P., Moslehi, J., Salem, J. E. 2022

  Abstract

  Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocarditis) may present similarly and/or overlap with other cardiac pathology including acute coronary syndrome presenting a challenge for prompt clinical diagnosis.An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery stenosis >70% in patients undergoing coronary angiogram.Among 261 patients with clinically suspected ICB-myocarditis who underwent a coronary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coronary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revascularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was marginally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057).CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diagnosis and treatment or more severe presentation of ICB-myocarditis.

  View details for DOI 10.1016/j.ejca.2022.07.018

  View details for PubMedID 36030143

• Plasma exchange for severe immune-related adverse events from checkpoint inhibitors: an early window of opportunity? Immunotherapy advances Katsumoto, T. R., Wilson, K. L., Giri, V. K., Zhu, H., Anand, S., Ramchandran, K. J., Martin, B. A., Yunce, M., Muppidi, S. 2022; 2 (1): ltac012

  Abstract

  Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several advanced malignancies leading to durable remission in a subset of patients. Their rapidly expanding use has led to an increased frequency of immune-related adverse events (irAEs). The pathogenesis of irAEs is poorly understood but may involve aberrant activation of T cells leading to inflammatory cytokine release or production of pathogenic antibodies leading to organ damage. Severe irAEs can be extremely debilitating and, in some cases, life threatening. IrAEs may not always be corticosteroid responsive or may require excessively high, often toxic, corticosteroid doses. Therapeutic plasma exchange (PLEX) is a treatment modality that has shown promising results for the management of certain severe irAEs, including irAEs that are not mentioned in current treatment guidelines. PLEX may attenuate ongoing irAEs and prevent delayed irAEs by accelerating clearance of the ICI, or by acutely removing pathogenic antibodies, cytokines, and chemokines. Here, we summarize examples from the literature in which PLEX was successfully used for the treatment of irAEs. We posit that timing may be a critical factor and that earlier utilization of PLEX for life-threatening irAEs may result in more favorable outcomes. In individuals at high risk for irAEs, the availability of PLEX as a potential therapeutic mitigation strategy may encourage life-saving ICI use or rechallenge. Future research will be critical to better define which indications are most amenable to PLEX, particularly to establish the optimal place in the sequence of irAE therapies and to assess the ramifications of ICI removal on cancer outcomes.

  View details for DOI 10.1093/immadv/ltac012

  View details for PubMedID 35814850

  View details for PubMedCentralID PMC9257781

• LATE ONSET IMMUNOTHERAPY-INDUCED MYOCARDITIS TWO YEARS AFTER CHECKPOINT INHIBITOR INITIATION Nguyen, A. T., Witteles, R. M., Zhu, H. 2022: S8-S9

  View details for DOI 10.1016/j.jaccao.2022.01.086

• Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms. Circulation. Genomic and precision medicine Lindholm, M. E., Jimenez-Morales, D., Zhu, H., Seo, K., Amar, D., Zhao, C., Raja, A., Madhvani, R., Abramowitz, S., Espenel, C., Sutton, S., Caleshu, C., Berry, G. J., Motonaga, K. S., Dunn, K., Platt, J., Ashley, E. A., Wheeler, M. T. 2021: CIRCGEN121003419

  Abstract

  BACKGROUND: ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel ACTN2 mutations to reveal insights into the physiological function of ACTN2.METHODS: Patients harboring ACTN2 protein-truncating variants were identified using a custom mutation pipeline. In patient-derived iPSC-cardiomyocytes, we investigated transcriptional profiles using RNA sequencing, contractile properties using video-based edge detection, and cellular hypertrophy using immunohistochemistry. Structural changes were analyzed through electron microscopy. For mechanistic studies, we used coimmunoprecipitation for ACTN2, followed by mass-spectrometry to investigate protein-protein interaction, and protein tagging followed by confocal microscopy to investigate introduction of truncated ACTN2 into the sarcomeres.RESULTS: Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc ultrastructure. In homozygous stop-gain cells, affinity-purification mass-spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins. Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 and GJA1, 2 sarcolemma-associated proteins, which may contribute to the clinical arrhythmic and relaxation defects. The causality of the stop-gain mutation was verified using CRISPR-Cas9 gene editing.CONCLUSIONS: Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of ACTN2 truncation as causative of disease.

  View details for DOI 10.1161/CIRCGEN.121.003419

  View details for PubMedID 34802252

• Immune checkpoint inhibitor cardiotoxicity: Breaking barriers in the cardiovascular immune landscape. Journal of molecular and cellular cardiology Zhu, H., Ivanovic, M., Nguyen, A., Nguyen, P. K., Wu, S. M. 2021

  Abstract

  Immune checkpoint inhibitors (ICI) have changed the landscape of cancer therapy, but their use carries a high risk of cardiac immune related adverse events (iRAEs). With the expanding utilization of ICI therapy, there is a growing need to understand the underlying mechanisms behind their anti-tumor activity as well as their immune-mediated toxicities. In this review, we will focus on clinical characteristics and immune pathways of ICI cardiotoxicity, with an emphasis on single-cell technologies used to gain insights in this field. We will focus on three key areas of ICI-mediated immune pathways, including the anti-tumor immune response, the augmentation of the immune response by ICIs, and the pathologic "autoimmune" response in some individuals leading to immune-mediated toxicity, as well as local factors in the myocardial immune environment predisposing to autoimmunity. Discerning the underlying mechanisms of these immune pathways is necessary to inform the development of targeted therapies for ICI cardiotoxicities and reduce treatment related morbidity and mortality.

  View details for DOI 10.1016/j.yjmcc.2021.07.006

  View details for PubMedID 34303670

• Immune Profiling and Causal Antigen Discovery in Mouse and Human Models of Immune Checkpoint Inhibitor-induced Myocarditis Zhu, H., Lee, D., Sarah, W., Galdos, F. X., D'Addabbo, J., Fowler, M. B., Reddy, S., Heather, W., Neal, J. W., Witteles, R., Maecker, H. T., Davis, M., Nguyen, P. K., Wu, S. M. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for DOI 10.1161/res.127.suppl_1.350

  View details for Web of Science ID 000606541500116

• Correction to: Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response. Current cardiology reports Zhu, H., Rhee, J., Cheng, P., Waliany, S., Chang, A., Witteles, R. M., Maecker, H., Davis, M. M., Nguyen, P. K., Wu, S. M. 2020; 22 (5): 36

  Abstract

  It has been pointed out that the second paragraph of the section "Treatments for SARS-CoV-2 Infection" contains an error. The original article has been corrected.

  View details for DOI 10.1007/s11886-020-01302-4

  View details for PubMedID 32405913

• Immune Profiling and Causal Antigen Discovery in Mouse and Human Models of Immune Checkpoint Inhibitor-induced Myocarditis Basic Cardiovascular Sciences (BCVS) Scientific Sessions Zhu, H., Lee, D., Waliany, S., Galdos, F., D'Addabbo, J., Fowler, M. B., Reddy, S., Wakelee, H., Neal, J. W., Witteles, R. M., Maecker, H. T., Davis, M. M., Nguyen, P. K., Wu, S. M. 2020
• Cardiovascular Risks in Patients with COVID-19: Potential Mechanisms and Areas of Uncertainty. Current cardiology reports Cheng, P. n., Zhu, H. n., Witteles, R. M., Wu, J. C., Quertermous, T. n., Wu, S. M., Rhee, J. W. 2020; 22 (5): 34

  Abstract

  COronaVirus Disease 2019 (COVID-19) has spread at unprecedented speed and scale into a global pandemic with cardiovascular risk factors and complications emerging as important disease modifiers. We aim to review available clinical and biomedical literature on cardiovascular risks of COVID-19.SARS-CoV2, the virus responsible for COVID-19, enters the cell via ACE2 expressed in select organs. Emerging epidemiological evidence suggest cardiovascular risk factors are associated with increased disease severity and mortality in COVID-19 patients. Patients with a more severe form of COVID-19 are also more likely to develop cardiac complications such as myocardial injury and arrhythmia. The true incidence of and mechanism underlying these events remain elusive. Cardiovascular diseases appear intricately linked with COVID-19, with cardiac complications contributing to the elevated morbidity/mortality of COVID-19. Robust epidemiologic and biologic studies are urgently needed to better understand the mechanism underlying these associations to develop better therapies.

  View details for DOI 10.1007/s11886-020-01293-2

  View details for PubMedID 32350632

• Low Wall Shear Stress Is Associated with Saphenous Vein Graft Stenosis in Patients with Coronary Artery Bypass Grafting. Journal of cardiovascular translational research Khan, M. O., Tran, J. S., Zhu, H. n., Boyd, J. n., Packard, R. R., Karlsberg, R. P., Kahn, A. M., Marsden, A. L. 2020

  Abstract

  Biomechanical forces may play a key role in saphenous vein graft (SVG) disease after coronary artery bypass graft (CABG) surgery. Computed tomography angiography (CTA) of 430 post-CABG patients were evaluated and 15 patients were identified with both stenosed and healthy SVGs for paired analysis. The stenosis was virtually removed, and detailed 3D models were reconstructed to perform patient-specific computational fluid dynamic (CFD) simulations. Models were processed to compute anatomic parameters, and hemodynamic parameters such as local and vessel-averaged wall shear stress (WSS), normalized WSS (WSS*), low shear area (LSA), oscillatory shear index (OSI), and flow rate. WSS* was significantly lower in pre-diseased SVG segments compared to corresponding control segments without disease (1.22 vs. 1.73, p = 0.012) and the area under the ROC curve was 0.71. No differences were observed in vessel-averaged anatomic or hemodynamic parameters between pre-stenosed and control whole SVGs. There are currently no clinically available tools to predict SVG failure post-CABG. CFD modeling has the potential to identify high-risk CABG patients who may benefit from more aggressive medical therapy and closer surveillance. Graphical Abstract.

  View details for DOI 10.1007/s12265-020-09982-7

  View details for PubMedID 32240496

• Immune Checkpoint Inhibitor Cardiotoxicity: Understanding Basic Mechanisms and Clinical Characteristics and Finding a Cure. Annual review of pharmacology and toxicology Waliany, S. n., Lee, D. n., Witteles, R. M., Neal, J. W., Nguyen, P. n., Davis, M. M., Salem, J. E., Wu, S. M., Moslehi, J. J., Zhu, H. n. 2020

  Abstract

  Immune checkpoint inhibitors (ICIs) attenuate mechanisms of self-tolerance in the immune system, enabling T cell responses to cancerous tissues and revolutionizing care for cancer patients. However, by lowering barriers against self-reactivity, ICIs often result in varying degrees of autoimmunity. Cardiovascular complications, particularly myocarditis but also arrhythmias, pericarditis, and vasculitis, have emerged as significant complications associated with ICIs. In this review, we examine the clinical aspects and basic science principles that underlie ICI-associated myocarditis and other cardiovascular toxicities. In addition, we discuss current therapeutic approaches. We believe a better mechanistic understanding of ICI-associated toxicities can lead to improved patient outcomes by reducing treatment-related morbidity. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 8, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for DOI 10.1146/annurev-pharmtox-010919-023451

  View details for PubMedID 32776859

• A Case of Early Immune Checkpoint Inhibitor Myocarditis Detected on Routine Troponin Monitoring Advancing the Cardiovascular Care of the Oncology Patient Zhu, H., Waliany, S., Neal, J., Wakelee, H., Wu, S. M., Witteles, R. M. 2020
• NOVEL ALPHA-ACTININ 2 MUTATIONS ARE ASSOCIATED WITH CARDIOMYOPATHY AND HYPERTROPHY IN HUMAN CARDIAC TISSUE AND IPSC-DERIVED CARDIOMYOCYTES Lindholm, M., Zhu, H., Huang, Y., Ashley, E. A., Wheeler, M. ELSEVIER SCIENCE INC. 2019: 1027

  View details for Web of Science ID 000460565901040

• Computational Fluid Dynamics of CABG Patients: CTA-derived Hemodynamic and Anatomic Predictors of Vein Graft Failure. Society of Cardiovascular Computed Tomography. Kahn, M., Tran, J., Zhu, H., Packard, R., Karlsberg, R., Marsden, A. 2019
• Computational Fluid Dynamics (BypassCFD) Trumps Anatomic Predictors of Saphenous Vein Graft Failure in CABG Patients Khan, M., Tran, J. S., Zhu, H., Packard, R. S., Karlsberg, R. P., Kahn, A., Marsden, A. L. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619404279

• Computational Fluid Dynamics (BypassCFD) Trumps Anatomic Predictors of Saphenous Vein Graft Failure in CABG Patients American Heart Association Kahn, O., Tran, J. S., Zhu, H., Packard, R. S., Karlsberg, R. P., Kahn, A., Marsden, A. 2018
• Sinoatrial node toxicity after stereotactic ablative radiation therapy to lung tumors. Practical radiation oncology Qian, Y. n., Zhu, H. n., Pollom, E. L., Durkee, B. Y., Chaudhuri, A. A., Gensheimer, M. F., Diehn, M. n., Shultz, D. B., Loo, B. W. 2017

  Abstract

  Stereotactic ablative radiation therapy (SABR) is an established treatment for selected lung tumors. Sinoatrial node (SAN) toxicity after thoracic SABR has not been reported in the literature. We sought to understand the risk of SAN toxicity owing to incidental dose to the SAN from SABR.We conducted a retrospective review of patients with early-stage lung cancer or limited pulmonary metastases who underwent thoracic SABR to a right-sided central lung tumor (within 2 cm of the mainstem bronchus or other mediastinal structures) between January 2008 and December 2014, analyzed a subset whose treatment imparted dose to the SAN exceeding 10% of the prescription dose, and examined patient and treatment dosimetric characteristics. Mean follow-up interval was 28 months. Time to toxicity was defined from start of SABR.Of 47 patients with central tumors in the right lung treated with SABR reviewed, 13 met our study criteria. A contouring atlas of regional cardiac anatomy was created. One patient treated with SABR for non-small cell lung cancer at the right hilum developed symptomatic sick sinus syndrome, requiring pacemaker placement 6 months after treatment. Her acute presentation and short interval between SABR and onset of symptoms suggest that SAN toxicity was likely due to radiation-induced injury. Both her age and mean dose to her SAN were the third highest in our cohort. She remained free from cancer progression at 24 months' follow-up. Twelve additional patients who received significant dose to the SAN from SABR did not develop toxicity.While uncommon, SAN toxicity from SABR to right-sided central thoracic tumors should be recognized and followed in future studies.

  View details for PubMedID 28669706

• ACTN2 Mutations Are Associated With Cardiomyopathy and Cardiomyocyte Hypertrophy Zhu, H., Ashley, E., Wheeler, M. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000396815606012

• Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program. Proceedings of the National Academy of Sciences of the United States of America Morrison-Nozik, A., Anand, P., Zhu, H., Duan, Q., Sabeh, M., Prosdocimo, D. A., Lemieux, M. E., Nordsborg, N., Russell, A. P., MacRae, C. A., Gerber, A. N., Jain, M. K., Haldar, S. M. 2015; 112 (49): E6780-9

  Abstract

  Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.

  View details for DOI 10.1073/pnas.1512968112

  View details for PubMedID 26598680

  View details for PubMedCentralID PMC4679037

• Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism. The Journal of biological chemistry Prosdocimo, D. A., Anand, P., Liao, X., Zhu, H., Shelkay, S., Artero-Calderon, P., Zhang, L., Kirsh, J., Moore, D., Rosca, M. G., Vazquez, E., Kerner, J., Akat, K. M., Williams, Z., Zhao, J., Fujioka, H., Tuschl, T., Bai, X., Schulze, P. C., Hoppel, C. L., Jain, M. K., Haldar, S. M. 2014; 289 (9): 5914-24

  Abstract

  The mammalian heart, the body's largest energy consumer, has evolved robust mechanisms to tightly couple fuel supply with energy demand across a wide range of physiologic and pathophysiologic states, yet, when compared with other organs, relatively little is known about the molecular machinery that directly governs metabolic plasticity in the heart. Although previous studies have defined Kruppel-like factor 15 (KLF15) as a transcriptional repressor of pathologic cardiac hypertrophy, a direct role for the KLF family in cardiac metabolism has not been previously established. We show in human heart samples that KLF15 is induced after birth and reduced in heart failure, a myocardial expression pattern that parallels reliance on lipid oxidation. Isolated working heart studies and unbiased transcriptomic profiling in Klf15-deficient hearts demonstrate that KLF15 is an essential regulator of lipid flux and metabolic homeostasis in the adult myocardium. An important mechanism by which KLF15 regulates its direct transcriptional targets is via interaction with p300 and recruitment of this critical co-activator to promoters. This study establishes KLF15 as a key regulator of myocardial lipid utilization and is the first to implicate the KLF transcription factor family in cardiac metabolism.

  View details for DOI 10.1074/jbc.M113.531384

  View details for PubMedID 24407292

  View details for PubMedCentralID PMC3937660

• Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation. Proceedings of the National Academy of Sciences of the United States of America Haldar, S. M., Jeyaraj, D., Anand, P., Zhu, H., Lu, Y., Prosdocimo, D. A., Eapen, B., Kawanami, D., Okutsu, M., Brotto, L., Fujioka, H., Kerner, J., Rosca, M. G., McGuinness, O. P., Snow, R. J., Russell, A. P., Gerber, A. N., Bai, X., Yan, Z., Nosek, T. M., Brotto, M., Hoppel, C. L., Jain, M. K. 2012; 109 (17): 6739-44

  Abstract

  The ability of skeletal muscle to enhance lipid utilization during exercise is a form of metabolic plasticity essential for survival. Conversely, metabolic inflexibility in muscle can cause organ dysfunction and disease. Although the transcription factor Kruppel-like factor 15 (KLF15) is an important regulator of glucose and amino acid metabolism, its endogenous role in lipid homeostasis and muscle physiology is unknown. Here we demonstrate that KLF15 is essential for skeletal muscle lipid utilization and physiologic performance. KLF15 directly regulates a broad transcriptional program spanning all major segments of the lipid-flux pathway in muscle. Consequently, Klf15-deficient mice have abnormal lipid and energy flux, excessive reliance on carbohydrate fuels, exaggerated muscle fatigue, and impaired endurance exercise capacity. Elucidation of this heretofore unrecognized role for KLF15 now implicates this factor as a central component of the transcriptional circuitry that coordinates physiologic flux of all three basic cellular nutrients: glucose, amino acids, and lipids.

  View details for DOI 10.1073/pnas.1121060109

  View details for PubMedID 22493257

  View details for PubMedCentralID PMC3340075

• Elevated fibroblast growth factor-2 increases tumor necrosis factor-alpha induced endothelial cell death in high glucose. Journal of cellular physiology Clyne, A. M., Zhu, H., Edelman, E. R. 2008; 217 (1): 86-92

  Abstract

  Glucose and tumor necrosis factor-alpha (TNFalpha) concentrations are elevated in diabetes. Both of these factors correlate with diabetic vasculopathy and endothelial cell apoptosis, yet their combined effects have not been measured. We have previously shown that the angiogenic growth factor fibroblast growth factor-2 (FGF-2), which is generally protective against endothelial cell death, is similarly elevated in high glucose conditions. We therefore investigated the effect of TNFalpha on endothelial cell death under normal and elevated glucose conditions, with a particular focus on FGF-2. Porcine aortic endothelial cells were cultured in 5 and 30 mM glucose and stimulated with TNFalpha, together with FGF-2 or a neutralizing FGF-2 antibody. Cell death was measured via cell counts or an annexin apoptotic assay, and cell cycle phase was determined by propidium iodide labeling. TNFalpha-induced endothelial cell death increased for cells in high glucose, and cell death was enhanced with increasing FGF-2 exposure and negated by a neutralizing FGF-2 antibody. Endothelial cells were most susceptible to TNFalpha-induced cell death when stimulated with FGF-2 18 h prior to TNFalpha, corresponding to cell entry into S phase of the proliferative cycle. The FGF-2 associated increase in TNFalpha-induced cell death was negated by blocking cell entry into S phase. Endothelial cell release of FGF-2 in high glucose leads to cell cycle progression, which makes cells more susceptible to TNFalpha-induced cell death. These data suggest that growth factor outcomes in high glucose depend on secondary mediators such as cytokines and stimulation cell cycle timing.

  View details for DOI 10.1002/jcp.21476

  View details for PubMedID 18446810

  View details for PubMedCentralID PMC2838244

• A porous photocurable elastomer for cell encapsulation and culture. Biomaterials Gerecht, S., Townsend, S. A., Pressler, H., Zhu, H., Nijst, C. L., Bruggeman, J. P., Nichol, J. W., Langer, R. 2007; 28 (32): 4826-35

  Abstract

  Encapsulating cells within a polymer matrix creates a three-dimensional (3D) scaffold that may more accurately represent the native microenvironment and cell organization. Here we report a porous scaffold prepared from a photocurable elastomer, poly(glycerolco-sebacate)-acrylate (PGSA). The scaffold porosity, swelling, mass loss, toxicity and mechanical properties, suggest that porous PGSA could be used to support the growth and differentiation of encapsulated cells. Neuroblastoma (NB) and human embryonic stem cells (hESCs) were encapsulated into the matrix and found to adhere to the material and interact with each other within 24h. After 7 days, encapsulated NB cells were found to grow, and form matrix fibrils and tissue. Undifferentiated hESCs proliferated and differentiated in the PGSA scaffold. In vivo experiments showed that both porous scaffolds have similar biocompatibility profiles as non-porous PGSA, but porous PGSA promotes tissue ingrowth, as compared to non-porous PGSA. We therefore propose that porous PGSA scaffolds can provide a logistical template for 3D growth of cells and tissue engineering.

  View details for DOI 10.1016/j.biomaterials.2007.07.039

  View details for PubMedID 17692371

• Characterization of Actin as a Cofactor for the Adenovirus Proteinase. Annual Research Exhibition at Brookhaven National Lab. Zhu, H., McGrat, W., Walter, M. 2007