Dr. Zhu is an Assistant Professor of Medicine whose clinical and research expertise focuses on cardio-oncology and cardio-immunology. She specializes in the cardiovascular care of patients undergoing therapies for cancer, with a particular focus on the effects of immunotherapies on the heart. She received a bioengineering degree from MIT, medical degree from Case Western Reserve University, and completed clinical cardiology fellowship and internal medicine residency training at Stanford University School of Medicine. Dr. Zhu’s laboratory focuses on myocarditis, cardiac inflammation, and the effects of cancer therapeutics on the cardiovascular system. Her current research employs clinical data, bio-banked samples, and in vivo/in vitro preclinical models in combination with single-cell technologies to study immune-based toxicities in the heart. Dr. Zhu's clinic sees cardio-oncology and cardio-immunology patients and her lab focuses on devising new methods for minimizing cardiovascular complications in the cancer and autoimmune patient populations.
- Cardiovascular Disease
Director, Stanford Translational Cardio-Oncology (2022 - Present)
Co-Director, Stanford Immune Related Toxicity Working Group (2022 - Present)
Honors & Awards
Stanford Cardiovascular Institute (CVI) Seed Grant, Stanford Cardiovascular Institute (CVI) (9/2023)
Stanford Cardiovascular Institute (CVI) Manuscript Award, Stanford Cardiovascular Institute (CVI) (1/2023)
NIH K08 Mentored Clinical Scientist Research Career Development Award, National Institute of Health (NIH) (2022-)
Melvin L. Marcus Early Career Investigator Award Finalist, American Heart Association (AHA) - Basic Cardiovascular Sciences (BCVS) (2021)
Gerald Reaven Basic Science Research Award, Stanford University (2020)
Sarnoff Scholar Career Development Award, Sarnoff Cardiovascular Foundation (2020)
Sanofi Innovation Awards (iAwards), Sanofi (2019-2021)
NIH F32 Ruth Kirschstein National Research Service Award Grant, National Institute of Health (NIH) (2019)
Stanford Cancer Institute (SCI) Innovation Award, Stanford Cancer Institute (SCI) (2019)
NIH Loan Repayment Award, National Institute of Health (NIH) (7/2019)
Alpha Omega Alpha (AOA) Member, Alpha Omega Alpha (AOA) (2014)
Myron F. Kanter and Lawrence J. Kanter Endowment Fund Award, Myron F. Kanter and Lawrence J. Kanter Foundation (2014)
Sarnoff Cardiovascular Research Foundation Fellowship, Sarnoff Cardiovascular Foundation (2012-2013)
Irwin H. Lepow Research Award, Irwin H. Lepow Research Foundation (2011)
American Federation of Aging Research (AFAR) Grant Recipient, American Federation of Aging Research (AFAR) (2010)
Boards, Advisory Committees, Professional Organizations
Assistant Editor, JACC: CardioOncology (2020 - Present)
Committee Member, AHA Statement on Preclinical Models in Cardio-Oncology Writing Group (2020 - Present)
Cardio-Oncology Subcommittee Member, American Heart Association (AHA) (2019 - Present)
Committee Member, American College of Cardiology Cardio-Oncology - California Chapter (2020 - Present)
Member, Society of Cardiovascular Computed Tomography (SCCT) (2019 - Present)
Member, American Society of Echocardiography (2019 - Present)
Board Certification: National Board of Echocardiography, Adult Echocardiography (2019)
Board Certification: American Board of Internal Medicine, Cardiovascular Disease (2020)
Board Certification, American College of Cardiology/ABIM, Cardiovascular Disease (2020)
Fellowship: Stanford University Cardiovascular Medicine Fellowship (2020) CA
Board Certification, Society of Cardiovascular Computer Tomography (SCCT), Cardiac CT (2019)
Board Certification: American Board of Internal Medicine, Internal Medicine (2017)
Residency: Stanford University Internal Medicine Residency (2017) CA
Medical Education: Case Western Reserve School of Medicine (2014) OH
Residency, Stanford University, Internal Medicine (2017)
Doctor of Medicine, Case Western Reserve University School of Medicine, Medicine (2014)
Bachelor of Science, Massachusetts Institute of Technology (MIT), Biological Engineering (2009)
Sean Wu, Han Zhu, Patricia Nguyen. "United States Patent 63/235,580 IDENTIFICATION OF PATHOGENIC IMMUNE CELL SUBSETS IN CHECKPOINT INHIBITOR-INDUCED MYOCARDITIS", Leland Stanford Junior University, Aug 20, 2021
Pilot Study for Black Men With Prostate Cancer: Optimization Of Mental and Heart Health, the BOOM-Heart Study
Pilot study to determine the feasibility of providing psychosocial and cardiac rehabilitation services to address socioeconomic health disparities and improve wellbeing for black men with prostate cancer.
The potential of auto-antigen-guided treatment of immune checkpoint inhibitor-mediated myocarditis.
Med (New York, N.Y.)
2023; 4 (1): 13-14
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
Osimertinib-Associated Cardiomyopathy In Patients With Non-Small Cell Lung Cancer: A Case Series
View details for DOI 10.1016/j.jaccao.2023.07.006
The Role of Single-Cell Profiling and Deep Immunophenotyping in Understanding Immune Therapy Cardiotoxicity.
2022; 4 (5): 629-634
• 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.
2022; 13 (1): 5271
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.
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
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 2021; 3 (1): 137–39
Preclinical Models of Cancer Therapy-Associated Cardiovascular Toxicity: A Scientific Statement From the American Heart Association.
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
Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis.
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
OSIMERTINIB-ASSOCIATED CARDIOMYOPATHY: A RETROSPECTIVE ANALYSIS OF THE STANFORD NON-SMALL CELL LUNG CANCER PATIENT COHORT
ELSEVIER SCIENCE INC. 2023: 411
View details for Web of Science ID 000990866100412
ACUTE CARDIOMYOPATHY AFTER INITIATION OF CABOZANTINIB, A MULTITYROSINE KINASE INHIBITOR
ELSEVIER SCIENCE INC. 2023: 2670
View details for Web of Science ID 000990866102681
Pharmacovigilance Analysis of HeartFailure Associated With Anti-HER2 Monotherapies and Combination Regimens for Cancer.
2023; 5 (1): 85-98
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
- Pharmacovigilance Analysis of Heart Failure Associated With Anti-HER2 Monotherapies and Combination Regimens for Cancer Jacc: CardioOncology 2023; 5 (1): 85-98
- Late-Onset Immunotherapy-Induced Myocarditis 2 Years After Checkpoint Inhibitor Initiation. JACC. CardioOncology 2022; 4 (5): 727-730
Coronary artery disease and revascularization associated with immune checkpoint blocker myocarditis: Report from an international registry.
European journal of cancer (Oxford, England : 1990)
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?
2022; 2 (1): ltac012
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
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
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
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 LIPPINCOTT WILLIAMS & WILKINS. 2020
- Correction to: Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response. Current cardiology reports 2020; 22 (5): 36
Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response
Curr Cardiol Rep
2020; 22 (5)
View details for DOI 10.1007/s11886-020-01292-3
- A Case of Early Immune Checkpoint Inhibitor Myocarditis Detected on Routine Troponin Monitoring Advancing the Cardiovascular Care of the Oncology Patient 2020
- Immune Profiling and Causal Antigen Discovery in Mouse and Human Models of Immune Checkpoint Inhibitor-induced Myocarditis Basic Cardiovascular Sciences (BCVS) Scientific Sessions 2020
Cardiovascular Risks in Patients with COVID-19: Potential Mechanisms and Areas of Uncertainty.
Current cardiology reports
2020; 22 (5): 34
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
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
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
NOVEL ALPHA-ACTININ 2 MUTATIONS ARE ASSOCIATED WITH CARDIOMYOPATHY AND HYPERTROPHY IN HUMAN CARDIAC TISSUE AND IPSC-DERIVED CARDIOMYOCYTES
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. 2019
Computational Fluid Dynamics (BypassCFD) Trumps Anatomic Predictors of Saphenous Vein Graft Failure in CABG Patients
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 2018
Sinoatrial node toxicity after stereotactic ablative radiation therapy to lung tumors.
Practical radiation oncology
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
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
2015; 112 (49): E6780-9
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
miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling.
2015; 21 (4): 584-95
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
Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism.
The Journal of biological chemistry
2014; 289 (9): 5914-24
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
2012; 109 (17): 6739-44
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
2008; 217 (1): 86-92
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.
2007; 28 (32): 4826-35
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. 2007