Dr. Cheng is a Cardiologist at Stanford University School of Medicine in the Department of Medicine and a member of the Cardiovascular Research Institute. Dr. Cheng received his BEng in Chemical Engineering and BSc in biology at MIT. He subsequently completed his MD/PhD at UCSF working in the Srivastava lab studying how extracellular morphogenic signals affect cardiac development and fate determination of cardiac progenitors. Dr. Cheng completed internal medicine residency and cardiology fellowship at Stanford. His current clinical focus is in amyloidosis and cardio-oncology. During his post doctoral research in the Quertermous lab, he pioneered the application of single cell transcriptomic and epigenetic techniques to study human vascular diseases including atherosclerosis and aneurysm, and applied these techniques to investigate molecular mechanisms behind genetic risk factors for several human vascular diseases including atherosclerosis, and aortopathies such as Marfan's and Loey-Dietz syndrome.

The Cheng lab takes a patient-to-bench-to-bedside approach to science. The lab focuses on elucidating new pathogenic mechanisms of human vascular diseases through combing human genetics and primary vascular disease tissues, with high-resolution transcriptomic and epigenetic profiling to generate novel hypothesis that are then tested in a variety of in vitro and in vivo models. The lab is focused on two broad questions: (1) understanding the biological underpinning of the differences in diseases propensities of different arterial segments in an individual (i.e. why do you have atherosclerosis and aneurysms in certain segments but not others), and (2) understanding the role of perivascular fibroblast in human vascular diseases.

Clinical Focus

  • Amyloidosis
  • Cardio-Oncology
  • Cardiovascular Disease

Academic Appointments

Honors & Awards

  • Louis N. and Arnold M. Katz Basic Research Prize, American Heart Association (11/2021)
  • K08 NIH Career Development Award, NIH/NHLBI (8/2020-7/2025)
  • AHA Career Development Award, American Heart Association (1/2021-1/2024)
  • Gerald Reaven Award for Basic Science, Stanford University Dept of Internal Medicine (2019)
  • Ruth L. Kirschtein NRSA NIH Postdoctoral Fellowship (F32), NIH / NHLBI (2018-2020)
  • Timothy F. Beckett, Jr. Award for Excellence in Teaching by a Medicine Fellow, Stanford Univ. Dept. of Internal Medicine (2017)

Professional Education

  • Board Certification: American Board of Internal Medicine, Cardiovascular Disease (2020)
  • Board Certification, American Board of Internal Medicine - Cardiovascular Medicine, Cardiovascular Medicine/Cardiology (2021)
  • Fellowship: Stanford University Cardiovascular Medicine Fellowship (2020) CA
  • Board Certification: American Board of Internal Medicine, Internal Medicine (2017)
  • Residency: Stanford University Internal Medicine Residency (2016) CA
  • Medical Education: University of California at San Francisco School of Medicine (2014) CA
  • Fellow, Cardiology (2020)
  • Resident, Stanford Internal Medicine (2016)
  • MD, PhD, University of California, San Francisco (2014)

2023-24 Courses

All Publications

  • Genome-Wide Genetic Associations Prioritize Evaluation of Causal Mechanisms of Atherosclerotic Disease Risk. Arteriosclerosis, thrombosis, and vascular biology Quertermous, T., Li, D. Y., Weldy, C. S., Ramste, M., Sharma, D., Monteiro, J. P., Gu, W., Worssam, M. D., Palmisano, B. T., Park, C. Y., Cheng, P. 2024; 44 (2): 323-327


    The goal of this review is to discuss the implementation of genome-wide association studies to identify causal mechanisms of vascular disease risk.The history of genome-wide association studies is described, the use of imputation and the creation of consortia to conduct meta-analyses with sufficient power to arrive at consistent associated loci for vascular disease. Genomic methods are described that allow the identification of causal variants and causal genes and how they impact the disease process. The power of single-cell analyses to promote genome-wide association studies of causal gene function is described.Genome-wide association studies represent a paradigm shift in the study of cardiovascular disease, providing identification of genes, cellular phenotypes, and disease pathways that empower the future of targeted drug development.

    View details for DOI 10.1161/ATVBAHA.123.319480

    View details for PubMedID 38266112

  • Smad3 regulates smooth muscle cell fate and mediates adverse remodeling and calcification of the atherosclerotic plaque. Nature cardiovascular research Cheng, P., Wirka, R. C., Kim, J. B., Kim, H. J., Nguyen, T., Kundu, R., Zhao, Q., Sharma, D., Pedroza, A., Nagao, M., Iyer, D., Fischbein, M. P., Quertermous, T. 2022; 1 (4): 322-333


    Atherosclerotic plaques consist mostly of smooth muscle cells (SMC), and genes that influence SMC phenotype can modulate coronary artery disease (CAD) risk. Allelic variation at 15q22.33 has been identified by genome-wide association studies to modify the risk of CAD and is associated with the expression of SMAD3 in SMC. However, the mechanism by which this gene modifies CAD risk remains poorly understood. Here we show that SMC-specific deletion of Smad3 in a murine atherosclerosis model resulted in greater plaque burden, more outward remodelling and increased vascular calcification. Single-cell transcriptomic analyses revealed that loss of Smad3 altered SMC transition cell state toward two fates: a SMC phenotype that governs both vascular remodelling and recruitment of inflammatory cells, as well as a chondromyocyte fate. Together, the findings reveal that Smad3 expression in SMC inhibits the emergence of specific SMC phenotypic transition cells that mediate adverse plaque features, including outward remodelling, monocyte recruitment, and vascular calcification.

    View details for DOI 10.1038/s44161-022-00042-8

    View details for PubMedID 36246779

    View details for PubMedCentralID PMC9560061

  • High-Throughput Precision Phenotyping of Left Ventricular Hypertrophy With Cardiovascular Deep Learning. JAMA cardiology Duffy, G., Cheng, P. P., Yuan, N., He, B., Kwan, A. C., Shun-Shin, M. J., Alexander, K. M., Ebinger, J., Lungren, M. P., Rader, F., Liang, D. H., Schnittger, I., Ashley, E. A., Zou, J. Y., Patel, J., Witteles, R., Cheng, S., Ouyang, D. 2022


    Importance: Early detection and characterization of increased left ventricular (LV) wall thickness can markedly impact patient care but is limited by under-recognition of hypertrophy, measurement error and variability, and difficulty differentiating causes of increased wall thickness, such as hypertrophy, cardiomyopathy, and cardiac amyloidosis.Objective: To assess the accuracy of a deep learning workflow in quantifying ventricular hypertrophy and predicting the cause of increased LV wall thickness.Design, Settings, and Participants: This cohort study included physician-curated cohorts from the Stanford Amyloid Center and Cedars-Sinai Medical Center (CSMC) Advanced Heart Disease Clinic for cardiac amyloidosis and the Stanford Center for Inherited Cardiovascular Disease and the CSMC Hypertrophic Cardiomyopathy Clinic for hypertrophic cardiomyopathy from January 1, 2008, to December 31, 2020. The deep learning algorithm was trained and tested on retrospectively obtained independent echocardiogram videos from Stanford Healthcare, CSMC, and the Unity Imaging Collaborative.Main Outcomes and Measures: The main outcome was the accuracy of the deep learning algorithm in measuring left ventricular dimensions and identifying patients with increased LV wall thickness diagnosed with hypertrophic cardiomyopathy and cardiac amyloidosis.Results: The study included 23 745 patients: 12 001 from Stanford Health Care (6509 [54.2%] female; mean [SD] age, 61.6 [17.4] years) and 1309 from CSMC (808 [61.7%] female; mean [SD] age, 62.8 [17.2] years) with parasternal long-axis videos and 8084 from Stanford Health Care (4201 [54.0%] female; mean [SD] age, 69.1 [16.8] years) and 2351 from CSMS (6509 [54.2%] female; mean [SD] age, 69.6 [14.7] years) with apical 4-chamber videos. The deep learning algorithm accurately measured intraventricular wall thickness (mean absolute error [MAE], 1.2 mm; 95% CI, 1.1-1.3 mm), LV diameter (MAE, 2.4 mm; 95% CI, 2.2-2.6 mm), and posterior wall thickness (MAE, 1.4 mm; 95% CI, 1.2-1.5 mm) and classified cardiac amyloidosis (area under the curve [AUC], 0.83) and hypertrophic cardiomyopathy (AUC, 0.98) separately from other causes of LV hypertrophy. In external data sets from independent domestic and international health care systems, the deep learning algorithm accurately quantified ventricular parameters (domestic: R2, 0.96; international: R2, 0.90). For the domestic data set, the MAE was 1.7 mm (95% CI, 1.6-1.8 mm) for intraventricular septum thickness, 3.8 mm (95% CI, 3.5-4.0 mm) for LV internal dimension, and 1.8 mm (95% CI, 1.7-2.0 mm) for LV posterior wall thickness. For the international data set, the MAE was 1.7 mm (95% CI, 1.5-2.0 mm) for intraventricular septum thickness, 2.9 mm (95% CI, 2.4-3.3 mm) for LV internal dimension, and 2.3 mm (95% CI, 1.9-2.7 mm) for LV posterior wall thickness. The deep learning algorithm accurately detected cardiac amyloidosis (AUC, 0.79) and hypertrophic cardiomyopathy (AUC, 0.89) in the domestic external validation site.Conclusions and Relevance: In this cohort study, the deep learning model accurately identified subtle changes in LV wall geometric measurements and the causes of hypertrophy. Unlike with human experts, the deep learning workflow is fully automated, allowing for reproducible, precise measurements, and may provide a foundation for precision diagnosis of cardiac hypertrophy.

    View details for DOI 10.1001/jamacardio.2021.6059

    View details for PubMedID 35195663

  • ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis Circulation Cheng, P., Wirka, R. C., Clarke, L., Zhao, Q., Kundu, R., Nguyen, T., Nair, S., Sharma, D., Kim, H., Shi, H., Assimes, T., Kim, J., Kundaje, A., Quertermous, T. 2022; 145 (6): 469–485


    Background: Smooth muscle cells (SMC) transition into a number of different phenotypes during atherosclerosis, including those that resemble fibroblasts and chondrocytes, and make up the majority of cells in the atherosclerotic plaque. To better understand the epigenetic and transcriptional mechanisms that mediate these cell state changes, and how they relate to risk for coronary artery disease (CAD), we have investigated the causality and function of transcription factors (TFs) at genome wide associated loci. Methods: We employed CRISPR-Cas 9 genome and epigenome editing to identify the causal gene and cell(s) for a complex CAD GWAS signal at 2q22.3. Subsequently, single-cell epigenetic and transcriptomic profiling in murine models and human coronary artery smooth muscle cells were employed to understand the cellular and molecular mechanism by which this CAD risk gene exerts its function. Results: CRISPR-Cas 9 genome and epigenome editing showed that the complex CAD genetic signals within a genomic region at 2q22.3 lie within smooth muscle long-distance enhancers for ZEB2, a TF extensively studied in the context of epithelial mesenchymal transition (EMT) in development and cancer. ZEB2 regulates SMC phenotypic transition through chromatin remodeling that obviates accessibility and disrupts both Notch and TGFβ signaling, thus altering the epigenetic trajectory of SMC transitions. SMC specific loss of ZEB2 resulted in an inability of transitioning SMCs to turn off contractile programing and take on a fibroblast-like phenotype, but accelerated the formation of chondromyocytes, mirroring features of high-risk atherosclerotic plaques in human coronary arteries. Conclusions: These studies identify ZEB2 as a new CAD GWAS gene that affects features of plaque vulnerability through direct effects on the epigenome, providing a new thereapeutic approach to target vascular disease.

    View details for DOI 10.1161/CIRCULATIONAHA.121.057789

  • Comprehensive Integration of Multiple Single-Cell Transcriptomic Datasets Defines Distinct Cell Populations and Their Phenotypic Changes in Murine Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology Sharma, D., DeForest Worssam, M., Pedroza, A. J., Dalal, A. R., Alemany, H., Kim, H. J., Kundu, R., Fischbein, M., Cheng, P., Wirka, R., Quertermous, T. 2023


    The application of single-cell transcriptomic (single-cell RNA sequencing) analysis to the study of atherosclerosis has provided unique insights into the molecular and genetic mechanisms that mediate disease risk and pathophysiology. However, nonstandardized methodologies and relatively high costs associated with the technique have limited the size and replication of existing data sets and created disparate or contradictory findings that have fostered misunderstanding and controversy.To address these uncertainties, we have performed a conservative integration of multiple published single-cell RNA sequencing data sets into a single meta-analysis, performed extended analysis of native resident vascular cells, and used in situ hybridization to map the disease anatomic location of the identified cluster cells. To investigate the transdifferentiation of smooth muscle cells to macrophage phenotype, we have developed a classifying algorithm based on the quantification of reporter transgene expression.The reporter gene expression tool indicates that within the experimental limits of the examined studies, transdifferentiation of smooth muscle cell to the macrophage lineage is extremely rare. Validated transition smooth muscle cell phenotypes were defined by clustering, and the location of these cells was mapped to lesion anatomy with in situ hybridization. We have also characterized 5 endothelial cell phenotypes and linked these cellular species to different vascular structures and functions. Finally, we have identified a transcriptomically unique cellular phenotype that constitutes the aortic valve.Taken together, these analyses resolve a number of outstanding issues related to differing results reported with vascular disease single-cell RNA sequencing studies, and significantly extend our understanding of the role of resident vascular cells in anatomy and disease.

    View details for DOI 10.1161/ATVBAHA.123.320030

    View details for PubMedID 38152886

  • 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


    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

  • 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
  • Early clinical outcomes and molecular smooth muscle cell phenotyping using a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome. The Journal of thoracic and cardiovascular surgery Pedroza, A. J., Cheng, P., Dalal, A. R., Baeumler, K., Kino, A., Tognozzi, E., Shad, R., Yokoyama, N., Nakamura, K., Mitchel, O., Hiesinger, W., MacFarlane, E. G., Fleischmann, D., Woo, Y. J., Quertermous, T., Fischbein, M. P. 2023


    Loeys-Dietz syndrome (LDS) patients demonstrate heightened risk of distal thoracic aortic events after valve-sparing aortic root replacement (VSARR). This study assesses the clinical risks and hemodynamic consequences of a prophylactic aortic arch replacement strategy in LDS and characterizes smooth muscle cell (SMC) phenotype in LDS aneurysmal and normal-sized downstream aorta.Patients with genetically confirmed LDS (n=8) underwent prophylactic aortic arch replacement during VSARR. 4D flow magnetic resonance imaging (MRI) studies were performed in n=4 LDS patients (VSARR+arch) and compared with both contemporary Marfan syndrome patients (VSARR only, n=5) and control patients (without aortopathy, n=5). Aortic tissues from n=4 LDS patients and n=2 organ donors were processed for anatomically segmented single-cell RNA sequencing (scRNAseq) and histologic assessment.LDS VSARR+arch patients had no deaths, major morbidity, or aortic events in median 2.00 years follow-up. 4D-MRI demonstrated altered flow parameters in post-operative aortopathy patients relative to controls, but no clear deleterious changes attributable to arch replacement. Integrated analysis of aortic scRNAseq data (>49,000 cells) identified a continuum of abnormal SMC phenotypic modulation in LDS defined by reduced contractility and enriched extracellular matrix synthesis, adhesion receptors, and transforming growth factor-beta signaling. These 'modulated SMCs' populated the LDS tunica media with gradually reduced density from the overtly aneurysmal root to the non-dilated arch.LDS patients demonstrated excellent surgical outcomes without overt downstream flow or shear stress disturbances after concomitant VSARR+arch operations. Abnormal SMC-mediated aortic remodeling occurs within the normal diameter, clinically at-risk LDS arch segment. These initial clinical and pathophysiologic findings support concomitant arch replacement in LDS.

    View details for DOI 10.1016/j.jtcvs.2023.07.023

    View details for PubMedID 37500053

  • Comparative arrhythmia patterns among patients on tyrosine kinase inhibitors. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing Wei, C., Fazal, M., Loh, A., Kapoor, R., Gomez, S. E., Shah, S., Rogers, A. J., Narayan, S. M., Wang, P. J., Witteles, R. M., Perino, A. C., Cheng, P., Rhee, J. W., Baykaner, T. 2023


    Tyrosine kinase inhibitors (TKIs) are widely used in the treatment of hematologic malignancies. Limited studies have shown an association between treatment-limiting arrhythmias and TKI, particularly ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. We sought to comprehensively assess the arrhythmia burden in patients receiving ibrutinib vs non-BTK TKI vs non-TKI therapies.We performed a retrospective analysis of consecutive patients who received long-term cardiac event monitors while on ibrutinib, non-BTK TKIs, or non-TKI therapy for a hematologic malignancy between 2014 and 2022.One hundred ninety-three patients with hematologic malignancies were included (ibrutinib = 72, non-BTK TKI = 46, non-TKI therapy = 75). The average duration of TKI therapy was 32 months in the ibrutinib group vs 64 months in the non-BTK TKI group (p = 0.003). The ibrutinib group had a higher prevalence of atrial fibrillation (n = 32 [44%]) compared to the non-BTK TKI (n = 7 [15%], p = 0.001) and non-TKI (n = 15 [20%], p = 0.002) groups. Similarly, the prevalence of non-sustained ventricular tachycardia was higher in the ibrutinib group (n = 31, 43%) than the non-BTK TKI (n = 8 [17%], p = 0.004) and non-TKI groups (n = 20 [27%], p = 0.04). TKI therapy was held in 25% (n = 18) of patients on ibrutinib vs 4% (n = 2) on non-BTK TKIs (p = 0.005) secondary to arrhythmias.In this large retrospective analysis of patients with hematologic malignancies, patients receiving ibrutinib had a higher prevalence of atrial and ventricular arrhythmias compared to those receiving other TKI, with a higher rate of treatment interruption due to arrhythmias.

    View details for DOI 10.1007/s10840-023-01575-z

    View details for PubMedID 37256462

  • Discovery of Transacting Long Noncoding RNAs That Regulate Smooth Muscle Cell Phenotype. Circulation research Shi, H., Nguyen, T., Zhao, Q., Cheng, P., Sharma, D., Kim, H. J., Brian Kim, J., Wirka, R., Weldy, C. S., Monteiro, J. P., Quertermous, T. 2023


    Smooth muscle cells (SMCs), the major cell type in atherosclerotic plaques, are vital in coronary artery diseases (CADs). Smooth muscle cell (SMC) phenotypic transition, which leads to the formation of various cell types in atherosclerotic plaques, is regulated by a network of genetic and epigenetic mechanisms and governs the risk of disease. The involvement of long noncoding RNAs (lncRNAs) has been increasingly identified in cardiovascular disease. However, SMC lncRNAs have not been comprehensively characterized, and their regulatory role in SMC state transition remains unknown.A discovery pipeline was constructed and applied to deeply strand-specific RNA sequencing from perturbed human coronary artery SMC with different disease-related stimuli, to allow for the detection of novel lncRNAs. The functional relevance of a select few novel lncRNAs were verified in vitro.We identified 4579 known and 13 655 de novo lncRNAs in human coronary artery SMC. Consistent with previous long noncoding RNA studies, these lncRNAs overall have fewer exons, are shorter in length than protein-coding genes (pcGenes), and have relatively low expression level. Genomic location of these long noncoding RNA is disproportionately enriched near CAD-related TFs (transcription factors), genetic loci, and gene regulators of SMC identity, suggesting the importance of their function in disease. Two de novo lncRNAs, ZEB-interacting suppressor (ZIPPOR) and TNS1-antisense (TNS1-AS2), were identified by our screen. Combining transcriptional data and in silico modeling along with in vitro validation, we identified CAD gene ZEB2 as a target through which these lncRNAs exert their function in SMC phenotypic transition.Expression of a large and diverse set of lncRNAs in human coronary artery SMC are highly dynamic in response to CAD-related stimuli. The dynamic changes in expression of these lncRNAs correspond to alterations in transcriptional programs that are relevant to CAD, suggesting a critical role for lncRNAs in SMC phenotypic transition and human atherosclerotic disease.

    View details for DOI 10.1161/CIRCRESAHA.122.321960

    View details for PubMedID 36852690

  • Molecular mechanisms of coronary artery disease risk at the PDGFD locus. Nature communications Kim, H., Cheng, P., Travisano, S., Weldy, C., Monteiro, J. P., Kundu, R., Nguyen, T., Sharma, D., Shi, H., Lin, Y., Liu, B., Haldar, S., Jackson, S., Quertermous, T. 2023; 14 (1): 847


    Genome wide association studies for coronary artery disease (CAD) have identified a risk locus at 11q22.3. Here, we verify with mechanistic studies that rs2019090 and PDGFD represent the functional variant and gene at this locus. Further, FOXC1/C2 transcription factor binding at rs2019090 is shown to promote PDGFD transcription through the CAD promoting allele. With single cell transcriptomic and histology studies with Pdgfd knockdown in an SMC lineage tracing male atherosclerosis mouse model we find that Pdgfd promotes expansion, migration, and transition of SMC lineage cells to the chondromyocyte phenotype. Pdgfd also increases adventitial fibroblast and pericyte expression of chemokines and leukocyte adhesion molecules, which is linked to plaque macrophage recruitment. Despite these changes there is no effect of Pdgfd deletion on overall plaque burden. These findings suggest that PDGFD mediates CAD risk by promoting deleterious phenotypic changes in SMC, along with an inflammatory response that is primarily focused in the adventitia.

    View details for DOI 10.1038/s41467-023-36518-9

    View details for PubMedID 36792607

  • 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
  • Tyrosine kinase inhibitor-associated ventricular arrhythmias: a case series and review of literature. Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing Fazal, M., Wei, C., Chuy, K. L., Hussain, K., Gomez, S. E., Ba, S. S., Pietrasik, G., Yadav, N., Ghazizadeh, Z., Kapoor, R., Witteles, R. M., Blackmon, A., Wang, P. J., John, R. M., Narayan, S. M., Cheng, P., Rhee, J., Baykaner, T. 2022


    BACKGROUND: Tyrosine kinase inhibitors (TKIs) have been increasingly used as first-line therapy in hematologic and solid-organ malignancies. Multiple TKIs have been linked with the development of cardiovascular complications, especially atrial arrhythmias, but data on ventricular arrhythmias (VAs) is scarce.METHODS: Herein we describe five detailed cases of VAs related to TKI use in patients with varied baseline cardiovascular risk factors between 2019 and 2022 at three centers. Individual chart review was conducted retrospectively.RESULTS: Patient ages ranged from 43 to 83years. Three patients were on Bruton's TKI (2 ibrutinib and 1 zanubrutinib) at the time of VAs; other TKIs involved were afatinib and dasatinib. Three patients had a high burden of non-sustained ventricular tachycardia (NSVT) requiring interventions, whereas two patients had sustained VAs. While all patients in our case series had significant improvement in VA burden after TKI cessation, two patients required new long-term antiarrhythmic drug therapy, and one had an implantable defibrillator cardioverter (ICD) placed due to persistent VAs after cessation of TKI therapy. One patient reinitiated TKI therapy after control of arrhythmia was achieved with antiarrhythmic drug therapy.CONCLUSIONS: Given the expanding long-term use of TKIs among a growing population of cancer patients, it is critical to acknowledge the association of TKIs with cardiovascular complications such as VAs, to characterize those at risk, and deploy preventive and therapeutic measures to avoid such complications and interference with oncologic therapy. Further efforts are warranted to develop monitoring protocols and optimal treatment strategies for TKI-induced VAs.

    View details for DOI 10.1007/s10840-022-01400-z

    View details for PubMedID 36411365

  • von Willebrand Factor Is Produced Exclusively by Endothelium, Not Neointima, in Occlusive Vascular Lesions in Both Pulmonary Hypertension and Atherosclerosis. Circulation Steffes, L. C., Cheng, P., Quertermous, T., Kumar, M. E. 2022; 146 (5): 429-431

    View details for DOI 10.1161/CIRCULATIONAHA.121.058427

    View details for PubMedID 35914017

  • Embryologic Origin Influences Smooth Muscle Cell Phenotypic Modulation Signatures in Murine Marfan Syndrome Aortic Aneurysm. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Dalal, A. R., Shad, R., Yokoyama, N., Nakamura, K., Cheng, P., Wirka, R. C., Mitchel, O., Baiocchi, M., Hiesinger, W., Quertermous, T., Fischbein, M. P. 2022: 101161ATVBAHA122317381


    BACKGROUND: Aortic root smooth muscle cells (SMC) develop from both the second heart field (SHF) and neural crest. Disparate responses to disease-causing Fbn1 variants by these lineages are proposed to promote focal aortic root aneurysm formation in Marfan syndrome (MFS), but lineage-stratified SMC analysis in vivo is lacking.METHODS: We generated SHF lineage-traced MFS mice and performed integrated multiomic (single-cell RNA and assay for transposase-accessible chromatin sequencing) analysis stratified by embryological origin. SMC subtypes were spatially identified via RNA in situ hybridization. Response to TWIST1 overexpression was determined via lentiviral transduction in human aortic SMCs.RESULTS: Lineage stratification enabled nuanced characterization of aortic root cells. We identified heightened SHF-derived SMC heterogeneity including a subset of Tnnt2-expressing cells distinguished by altered proteoglycan expression. MFS aneurysm-associated SMC phenotypic modulation was identified in both SHF-traced and nontraced (neural crest-derived) SMCs; however, transcriptomic responses were distinct between lineages. SHF-derived modulated SMCs overexpressed collagen synthetic genes and small leucine-rich proteoglycans while nontraced SMCs activated chondrogenic genes. These modulated SMCs clustered focally in the aneurysmal aortic root at the region of SHF/neural crest lineage overlap. Integrated RNA-assay for transposase-accessible chromatin analysis identified enriched Twist1 and Smad2/3/4 complex binding motifs in SHF-derived modulated SMCs. TWIST1 overexpression promoted collagen and SLRP gene expression in vitro, suggesting TWIST1 may drive SHF-enriched collagen synthesis in MFS aneurysm.CONCLUSIONS: SMCs derived from both SHF and neural crest lineages undergo phenotypic modulation in MFS aneurysm but are defined by subtly distinct transcriptional responses. Enhanced TWIST1 transcription factor activity may contribute to enriched collagen synthetic pathways SHF-derived SMCs in MFS.

    View details for DOI 10.1161/ATVBAHA.122.317381

    View details for PubMedID 35861960

  • Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self. Circulation research Roy Chowdhury, R., D'Addabbo, J., Huang, X., Veizades, S., Sasagawa, K., Louis, D. M., Cheng, P., Sokol, J., Jensen, A., Tso, A., Shankar, V., Wendel, B. S., Bakerman, I., Liang, G., Koyano, T., Fong, R., Nau, A., Ahmad, H., Gopakumar, J. K., Wirka, R., Lee, A., Boyd, J., Woo, Y. J., Quertermous, T., Gulati, G., Jaiswal, S., Chien, Y. H., Chan, C., Davis, M. M., Nguyen, P. K. 2022: 101161CIRCRESAHA121320090


    Once considered primarily a disorder of lipid deposition, coronary artery disease is an incurable, life-threatening disease that is now also characterized by chronic inflammation notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies.We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity.In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced, memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4

    View details for DOI 10.1161/CIRCRESAHA.121.320090

    View details for PubMedID 35430876

  • Effective Sphygmomanometer Based Non-invasive Central Venous Pressure Measurement In Hospitalized Heart Failure Patients Kawana, M., Cheng, P., Morimoto, H., Fowler, M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2022: S18
  • ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis. Circulation Cheng, P., Wirka, R. C., Clarke, L. S., Zhao, Q., Kundu, R., Nguyen, T., Nair, S., Sharma, D., Kim, H. J., Shi, H., Assimes, T., Kim, J. B., Kundaje, A., Quertermous, T. 2022


    Background: Smooth muscle cells (SMC) transition into a number of different phenotypes during atherosclerosis, including those that resemble fibroblasts and chondrocytes, and make up the majority of cells in the atherosclerotic plaque. To better understand the epigenetic and transcriptional mechanisms that mediate these cell state changes, and how they relate to risk for coronary artery disease (CAD), we have investigated the causality and function of transcription factors (TFs) at genome wide associated loci. Methods: We employed CRISPR-Cas 9 genome and epigenome editing to identify the causal gene and cell(s) for a complex CAD GWAS signal at 2q22.3. Subsequently, single-cell epigenetic and transcriptomic profiling in murine models and human coronary artery smooth muscle cells were employed to understand the cellular and molecular mechanism by which this CAD risk gene exerts its function. Results: CRISPR-Cas 9 genome and epigenome editing showed that the complex CAD genetic signals within a genomic region at 2q22.3 lie within smooth muscle long-distance enhancers for ZEB2, a TF extensively studied in the context of epithelial mesenchymal transition (EMT) in development and cancer. ZEB2 regulates SMC phenotypic transition through chromatin remodeling that obviates accessibility and disrupts both Notch and TGFβ signaling, thus altering the epigenetic trajectory of SMC transitions. SMC specific loss of ZEB2 resulted in an inability of transitioning SMCs to turn off contractile programing and take on a fibroblast-like phenotype, but accelerated the formation of chondromyocytes, mirroring features of high-risk atherosclerotic plaques in human coronary arteries. Conclusions: These studies identify ZEB2 as a new CAD GWAS gene that affects features of plaque vulnerability through direct effects on the epigenome, providing a new thereapeutic approach to target vascular disease.

    View details for DOI 10.1161/CIRCULATIONAHA.121.057789

    View details for PubMedID 34990206

  • Artificial intelligence applications in cardio-oncology: Leveraging high dimensional cardiovascular data. Frontiers in cardiovascular medicine Chen, H., Ouyang, D., Baykaner, T., Jamal, F., Cheng, P., Rhee, J. 2022; 9: 941148


    Growing evidence suggests a wide spectrum of potential cardiovascular complications following cancer therapies, leading to an urgent need for better risk-stratifying and disease screening in patients undergoing oncological treatment. As many cancer patients undergo frequent surveillance through imaging as well as other diagnostic testing, there is a wealth of information that can be utilized to assess one's risk for cardiovascular complications of cancer therapies. Over the past decade, there have been remarkable advances in applying artificial intelligence (AI) to analyze cardiovascular data obtained from electrocardiograms, echocardiograms, computed tomography, and cardiac magnetic resonance imaging to detect early signs or future risk of cardiovascular diseases. Studies have shown AI-guided cardiovascular image analysis can accurately, reliably and inexpensively identify and quantify cardiovascular risk, leading to better detection of at-risk or disease features, which may open preventive and therapeutic opportunities in cardio-oncology. In this perspective, we discuss the potential for the use of AI in analyzing cardiovascular data to identify cancer patients at risk for cardiovascular complications early in treatment which would allow for rapid intervention to prevent adverse cardiovascular outcomes.

    View details for DOI 10.3389/fcvm.2022.941148

    View details for PubMedID 35958422

  • Ibrutinib-associated atrial fibrillation treatment with catheter ablation. HeartRhythm case reports Kapoor, R., Fazal, M., Cheng, P., Witteles, R., Rhee, J., Baykaner, T. 2021; 7 (11): 713-716

    View details for DOI 10.1016/j.hrcr.2021.08.003

    View details for PubMedID 34820264

  • Arrhythmias Other Than Atrial Fibrillation in Those With an Irregular Pulse Detected With a Smartwatch: Findings From the Apple Heart Study. Circulation. Arrhythmia and electrophysiology Perino, A. C., Gummidipundi, S. E., Lee, J., Hedlin, H., Garcia, A., Ferris, T., Balasubramanian, V., Gardner, R. M., Cheung, L., Hung, G., Granger, C. B., Kowey, P., Rumsfeld, J. S., Russo, A. M., True Hills, M., Talati, N., Nag, D., Tsay, D., Desai, S., Desai, M., Mahaffey, K. W., Turakhia, M. P., Perez, M. V. 2021: CIRCEP121010063


    The Apple watch irregular pulse detection algorithm was found to have a positive predictive value of 0.84 for identification of atrial fibrillation (AF). We sought to describe the prevalence of arrhythmias other than AF in those with an irregular pulse detected on a smartwatch.The Apple Heart Study investigated a smartwatch-based irregular pulse notification algorithm to identify AF. For this secondary analysis, we analyzed participants who received an ambulatory ECG patch after index irregular pulse notification. We excluded participants with AF identified on ECG patch and described the prevalence of other arrhythmias on the remaining participant ECG patches. We also reported the proportion of participants self-reporting subsequent AF diagnosis.Among 419 297 participants enrolled in the Apple Heart Study, 450 participant ECG patches were analyzed, with no AF on 297 ECG patches (66%). Non-AF arrhythmias (excluding supraventricular tachycardias <30 beats and pauses <3 seconds) were detected in 119 participants (40.1%) with ECG patches without AF. The most common arrhythmias were frequent PACs (burden ≥1% to <5%, 15.8%; ≥5% to <15%, 8.8%), atrial tachycardia (≥30 beats, 5.4%), frequent PVCs (burden ≥1% to <5%, 6.1%; ≥5% to <15%, 2.7%), and nonsustained ventricular tachycardia (4-7 beats, 6.4%; ≥8 beats, 3.7%). Of 249 participants with no AF detected on ECG patch and patient-reported data available, 76 participants (30.5%) reported subsequent AF diagnosis.In participants with an irregular pulse notification on the Apple Watch and no AF observed on ECG patch, atrial and ventricular arrhythmias, mostly PACs and PVCs, were detected in 40% of participants. Defining optimal care for patients with detection of incidental arrhythmias other than AF is important as AF detection is further investigated, implemented, and refined.

    View details for DOI 10.1161/CIRCEP.121.010063

    View details for PubMedID 34565178

  • Arrhythmia Patterns in Patients on Ibrutinib. Frontiers in cardiovascular medicine Fazal, M., Kapoor, R., Cheng, P., Rogers, A. J., Narayan, S. M., Wang, P., Witteles, R. M., Perino, A. C., Baykaner, T., Rhee, J. 1800; 8: 792310


    Introduction: Ibrutinib, a Bruton's tyrosine kinase inhibitor (TKI) used primarily in the treatment of hematologic malignancies, has been associated with increased incidence of atrial fibrillation (AF), with limited data on its association with other tachyarrhythmias. There are limited reports that comprehensively analyze atrial and ventricular arrhythmia (VA) burden in patients on ibrutinib. We hypothesized that long-term event monitors could reveal a high burden of atrial and VAs in patients on ibrutinib. Methods: A retrospective data analysis at a single center using electronic medical records database search tools and individual chart review was conducted to identify consecutive patients who had event monitors while on ibrutinib therapy. Results: Seventy-two patients were included in the analysis with a mean age of 76.9 ± 9.9 years and 13 patients (18%) had a diagnosis of AF prior to the ibrutinib therapy. During ibrutinib therapy, most common arrhythmias documented were non-AF supraventricular tachycardia (n = 32, 44.4%), AF (n = 32, 44%), and non-sustained ventricular tachycardia (n = 31, 43%). Thirteen (18%) patients had >1% premature atrial contraction burden; 16 (22.2%) patients had >1% premature ventricular contraction burden. In 25% of the patients, ibrutinib was held because of arrhythmias. Overall 8.3% of patients were started on antiarrhythmic drugs during ibrutinib therapy to manage these arrhythmias. Conclusions: In this large dataset of ambulatory cardiac monitors on patients treated with ibrutinib, we report a high prevalence of atrial and VAs, with a high incidence of treatment interruption secondary to arrhythmias and related symptoms. Further research is warranted to optimize strategies to diagnose, monitor, and manage ibrutinib-related arrhythmias.

    View details for DOI 10.3389/fcvm.2021.792310

    View details for PubMedID 35047578

  • Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm. Arteriosclerosis, thrombosis, and vascular biology Pedroza, A. J., Tashima, Y., Shad, R., Cheng, P., Wirka, R., Churovich, S., Nakamura, K., Yokoyama, N., Cui, J. Z., Iosef, C., Hiesinger, W., Quertermous, T., Fischbein, M. P. 2020: ATVBAHA120314670


    OBJECTIVE: To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from Fbn1C1041G/+ (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1C1041G/+ mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE-/- mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 (Serpine1) and Kruppel-like factor 4 (Klf4). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of Fbn1C1041G/+ SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young Fbn1C1041G/+ mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1C1041G/+ descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF (transforming growth factor)-beta-responsive genes correlated with SMC modulation in mouse and human data sets.CONCLUSIONS: Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-beta plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-beta signaling and Klf4 overexpression as potential upstream drivers of SMC modulation.

    View details for DOI 10.1161/ATVBAHA.120.314670

    View details for PubMedID 32698686

  • 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


    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

  • Molecular mechanisms of coronary disease revealed using quantitative trait loci for TCF21 binding, chromatin accessibility, and chromosomal looping. Genome biology Zhao, Q. n., Dacre, M. n., Nguyen, T. n., Pjanic, M. n., Liu, B. n., Iyer, D. n., Cheng, P. n., Wirka, R. n., Kim, J. B., Fraser, H. B., Quertermous, T. n. 2020; 21 (1): 135


    To investigate the epigenetic and transcriptional mechanisms of coronary artery disease (CAD) risk, as well as the functional regulation of chromatin structure and function, we create a catalog of genetic variants associated with three stages of transcriptional cis-regulation in primary human coronary artery vascular smooth muscle cells (HCASMCs).We use a pooling approach with HCASMC lines to map regulatory variants that mediate binding of the CAD-associated transcription factor TCF21 with ChIPseq studies (bQTLs), variants that regulate chromatin accessibility with ATACseq studies (caQTLs), and chromosomal looping with Hi-C methods (clQTLs). We examine the overlap of these QTLs and their relationship to smooth muscle-specific genes and transcription factors. Further, we use multiple analyses to show that these QTLs are highly associated with CAD GWAS loci and correlate to lead SNPs where they show allelic effects. By utilizing genome editing, we verify that identified functional variants can regulate both chromatin accessibility and chromosomal looping, providing new insights into functional mechanisms regulating chromatin state and chromosomal structure. Finally, we directly link the disease-associated TGFB1-SMAD3 pathway to the CAD-associated FN1 gene through a response QTL that modulates both chromatin accessibility and chromosomal looping.Together, these studies represent the most thorough mapping of multiple QTL types in a highly disease-relevant primary cultured cell type and provide novel insights into their functional overlap and mechanisms that underlie these genomic features and their relationship to disease risk.

    View details for DOI 10.1186/s13059-020-02049-5

    View details for PubMedID 32513244

  • The Environment-Sensing Aryl-Hydrocarbon Receptor Inhibits the Chondrogenic Fate of Modulated Smooth Muscle Cells in Atherosclerotic Lesions. Circulation Kim, J. B., Zhao, Q. n., Nguyen, T. n., Pjanic, M. n., Cheng, P. n., Wirka, R. n., Travisano, S. n., Nagao, M. n., Kundu, R. n., Quertermous, T. n. 2020


    Background: Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease (CAD) risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC. Methods: We combined RNA-Seq, ChIP-Seq, ATAC-Seq and in-vitro assays in human coronary artery SMC (HCASMC), with single-cell RNA-Seq (scRNA-Seq), histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease. Results: Genomic studies coupled with functional assays in cultured HCASMC revealed that AHR modulates HCASMC phenotype and suppresses ossification in these cells. Lineage tracing and activity tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMC in the atherosclerotic lesion cap. Furthermore, scRNA-Seq studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMC expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term "chondromyocytes" (CMC), were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMC in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout compared to wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses. Conclusions: Overall, we conclude that AHR promotes maintenance of lesion cap integrity and diminishes the disease related SMC-to-CMC transition in atherosclerotic tissues.

    View details for DOI 10.1161/CIRCULATIONAHA.120.045981

    View details for PubMedID 32441123

  • 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)
  • Outcomes in Patients With Cardiac Amyloidosis Undergoing Heart Transplantation. JACC. Heart failure Barrett, C. D., Alexander, K. M., Zhao, H. n., Haddad, F. n., Cheng, P. n., Liao, R. n., Wheeler, M. T., Liedtke, M. n., Schrier, S. n., Arai, S. n., Weisshaar, D. n., Witteles, R. M. 2020


    The purpose of this study is to report outcomes after heart transplantation in patients with cardiac amyloidosis based on a large single-center experience.Cardiac amyloidosis causes significant morbidity and mortality, often leading to restrictive cardiomyopathy, progressive heart failure, and death. Historically, heart transplantation outcomes have been worse in patients with cardiac amyloidosis compared with other heart failure populations, in part due to the systemic nature of the disease. However, several case series have suggested that transplantation outcomes may be better in the contemporary era, likely in part due to the availability of more effective light chain suppressive therapies for light chain amyloidosis.This study examined all patients seen between 2004 and 2017, either at the Stanford University Medical Center or the Kaiser Permanente Santa Clara Medical Center, who were diagnosed with cardiac amyloidosis and ultimately underwent heart transplantation. This study examined pre-transplantation characteristics and post-transplantation outcomes in this group compared with the overall transplantation population at our center.During the study period, 31 patients (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) underwent heart transplantation. Patients with ATTR amyloidosis were older, were more likely to be male, had worse baseline renal function, and had longer waitlist times compared with both patients with light chain amyloidosis and the overall transplantation population. Post-transplantation, there were no differences in post-operative bleeding, renal failure, infection, rejection, or malignancy. There was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications.In carefully selected patients with cardiac amyloidosis, heart transplantation can be an effective therapeutic option with outcomes similar to those transplanted for other causes of heart failure.

    View details for DOI 10.1016/j.jchf.2019.12.013

    View details for PubMedID 32387068

  • 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


    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

  • Coronary Disease Associated Gene TCF21 Inhibits Smooth Muscle Cell Differentiation by Blocking the Myocardin-Serum Response Factor Pathway. Circulation research Nagao, M., Lyu, Q., Zhao, Q., Wirka, R. C., Bagga, J., Nguyen, T., Cheng, P., Kim, J. B., Pjanic, M., Miano, J. M., Quertermous, T. 2019


    Rationale: The gene encoding transcription factor TCF21 has been linked to coronary artery disease (CAD) risk by human genome wide association studies (GWAS) in multiple racial ethnic groups. In murine models, Tcf21 is required for phenotypic modulation of smooth muscle cells (SMC) in atherosclerotic tissues and promotes a fibroblast phenotype in these cells. In humans, TCF21 expression inhibits risk for CAD. The molecular mechanism by which TCF21 regulates SMC phenotype is not known. Objective: To better understand how TCF21 affects SMC phenotype, we sought to investigate the possible mechanisms by which it regulates the lineage determining myocardin (MYOCD)-serum response factor (SRF) pathway. Methods and Results: Modulation of TCF21 expression in HCASMC revealed that TCF21 suppresses a broad range of SMC markers, as well as key SMC transcription factors MYOCD and SRF, at the RNA and protein level. We conducted chromatin immunoprecipitation (ChIP)-sequencing to map SRF binding sites in HCASMC, showing that binding is colocalized in the genome with TCF21, including at a novel enhancer in the SRF gene, and at the MYOCD gene promoter. In vitro genome editing indicated that the SRF enhancer CArG box regulates transcription of the SRF gene, and mutation of this conserved motif in the orthologous mouse SRF enhancer revealed decreased SRF expression in aorta and heart tissues. Direct TCF21 binding and transcriptional inhibition at co-localized sites were established by reporter gene transfection assays. Chromatin immunoprecipitation and protein co-immunoprecipitation studies provided evidence that TCF21 blocks MYOCD and SRF association by direct TCF21-MYOCD interaction. Conclusions: These data indicate that TCF21 antagonizes the MYOCD-SRF pathway through multiple mechanisms, further establishing a role for this CAD associated gene in fundamental SMC processes and indicating the importance of smooth muscle response to vascular stress and phenotypic modulation of this cell type in CAD risk.

    View details for DOI 10.1161/CIRCRESAHA.119.315968

    View details for PubMedID 31815603

  • TCF21 and AP-1 interact through epigenetic modifications to regulate coronary artery disease gene expression GENOME MEDICINE Zhao, Q., Wirka, R., Trieu Nguyen, Nagao, M., Cheng, P., Miller, C. L., Kim, J., Pjanic, M., Quertermous, T. 2019; 11
  • Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. The New England journal of medicine Perez, M. V., Mahaffey, K. W., Hedlin, H., Rumsfeld, J. S., Garcia, A., Ferris, T., Balasubramanian, V., Russo, A. M., Rajmane, A., Cheung, L., Hung, G., Lee, J., Kowey, P., Talati, N., Nag, D., Gummidipundi, S. E., Beatty, A., Hills, M. T., Desai, S., Granger, C. B., Desai, M., Turakhia, M. P., Apple Heart Study Investigators, Perez, M. V., Turakhia, M. P., Lhamo, K., Smith, S., Berdichesky, M., Sharma, B., Mahaffey, K., Parizo, J., Olivier, C., Nguyen, M., Tallapalli, S., Kaur, R., Gardner, R., Hung, G., Mitchell, D., Olson, G., Datta, S., Gerenrot, D., Wang, X., McCoy, P., Satpathy, B., Jacobsen, H., Makovey, D., Martin, A., Perino, A., O'Brien, C., Gupta, A., Toruno, C., Waydo, S., Brouse, C., Dorfman, D., Stein, J., Huang, J., Patel, M., Fleischer, S., Doll, E., O'Reilly, M., Dedoshka, K., Chou, M., Daniel, H., Crowley, M., Martin, C., Kirby, T., Brumand, M., McCrystale, K., Haggerty, M., Newberger, J., Keen, D., Antall, P., Holbrook, K., Braly, A., Noone, G., Leathers, B., Montrose, A., Kosowsky, J., Lewis, D., Finkelmeier, J. R., Bemis, K., Mahaffey, K. W., Desai, M., Talati, N., Nag, D., Rajmane, A., Desai, S., Caldbeck, D., Cheung, L., Granger, C., Rumsfeld, J., Kowey, P. R., Hills, M. T., Russo, A., Rockhold, F., Albert, C., Alonso, A., Wruck, L., Friday, K., Wheeler, M., Brodt, C., Park, S., Rogers, A., Jones, R., Ouyang, D., Chang, L., Yen, A., Dong, J., Mamic, P., Cheng, P., Shah, R., Lorvidhaya, P. 2019; 381 (20): 1909–17


    BACKGROUND: Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown.METHODS: Participants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10.RESULTS: We recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed - which had been applied, on average, 13 days after notification - atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events.CONCLUSIONS: The probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study number, NCT03335800.).

    View details for DOI 10.1056/NEJMoa1901183

    View details for PubMedID 31722151

  • Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk PLOS GENETICS Iyer, D., Zhao, Q., Wirka, R., Naravane, A., Trieu Nguyen, Liu, B., Nagao, M., Cheng, P., Miller, C. L., Kim, J., Pjanic, M., Quertermous, T. 2018; 14 (10)
  • What's in a Name? Factors That Influence the Usage of Generic Versus Trade Names for Cardiac Medications Among Healthcare Providers CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Ouyang, D., Tisdale, R., Cheng, P., Chi, J., Chen, J. H., Ashley, E. 2018; 11 (8)
  • Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk. PLoS genetics Iyer, D. n., Zhao, Q. n., Wirka, R. n., Naravane, A. n., Nguyen, T. n., Liu, B. n., Nagao, M. n., Cheng, P. n., Miller, C. L., Kim, J. B., Pjanic, M. n., Quertermous, T. n. 2018; 14 (10): e1007681


    Although numerous genetic loci have been associated with coronary artery disease (CAD) with genome wide association studies, efforts are needed to identify the causal genes in these loci and link them into fundamental signaling pathways. Recent studies have investigated the disease mechanism of CAD associated gene SMAD3, a central transcription factor (TF) in the TGFβ pathway, investigating its role in smooth muscle biology. In vitro studies in human coronary artery smooth muscle cells (HCASMC) revealed that SMAD3 modulates cellular phenotype, promoting expression of differentiation marker genes while inhibiting proliferation. RNA sequencing and chromatin immunoprecipitation sequencing studies in HCASMC identified downstream genes that reside in pathways which mediate vascular development and atherosclerosis processes in this cell type. HCASMC phenotype, and gene expression patterns promoted by SMAD3 were noted to have opposing direction of effect compared to another CAD associated TF, TCF21. At sites of SMAD3 and TCF21 colocalization on DNA, SMAD3 binding was inversely correlated with TCF21 binding, due in part to TCF21 locally blocking chromatin accessibility at the SMAD3 binding site. Further, TCF21 was able to directly inhibit SMAD3 activation of gene expression in transfection reporter gene studies. In contrast to TCF21 which is protective toward CAD, SMAD3 expression in HCASMC was shown to be directly correlated with disease risk. We propose that the pro-differentiation action of SMAD3 inhibits dedifferentiation that is required for HCASMC to expand and stabilize disease plaque as they respond to vascular stresses, counteracting the protective dedifferentiating activity of TCF21 and promoting disease risk.

    View details for PubMedID 30307970

  • Persistent Fever Can be Associated with Transient but Severe Hemophagocytic Lymphohistiocytosis (HLH) in Adult Recipients of Ventricular Assist Devices (VAD) for Treatment of Cardiomyopathy (CM) Martin, B., Cheng, P. A., Banerjee, D., Ha, R. AMER SOC HEMATOLOGY. 2016
  • YTIC Lymphohistiocytosis (HLH) in Adult Recipients of Ventricular Assist Devices (VADS) for Cardiomyopathy (CM) and Favorable Outcomes in Subsequent Orthotopic Heart Transplantation (OHT) Martin, B., Cheng, P., Ha-Tien, R., Banerjee, D. WILEY-BLACKWELL. 2016: S49
  • Fibronectin mediates mesendodermal cell fate decisions. Development (Cambridge, England) Cheng, P., Andersen, P., Hassel, D., Kaynak, B. L., Limphong, P., Juergensen, L., Kwon, C., Srivastava, D. 2013; 140 (12): 2587-96


    Non-cell-autonomous signals often play crucial roles in cell fate decisions during animal development. Reciprocal signaling between endoderm and mesoderm is vital for embryonic development, yet the key signals and mechanisms remain unclear. Here, we show that endodermal cells efficiently promote the emergence of mesodermal cells in the neighboring population through signals containing an essential short-range component. The endoderm-mesoderm interaction promoted precardiac mesoderm formation in mouse embryonic stem cells and involved endodermal production of fibronectin. In vivo, fibronectin deficiency resulted in a dramatic reduction of mesoderm accompanied by endodermal expansion in zebrafish embryos. This event was mediated by regulation of Wnt signaling in mesodermal cells through activation of integrin-β1. Our findings highlight the importance of the extracellular matrix in mediating short-range signals and reveal a novel function of endoderm, involving fibronectin and its downstream signaling cascades, in promoting the emergence of mesoderm.

    View details for DOI 10.1242/dev.089052

    View details for PubMedID 23715551

    View details for PubMedCentralID PMC3666385

  • MicroRNA-10 regulates the angiogenic behavior of zebrafish and human endothelial cells by promoting vascular endothelial growth factor signaling. Circulation research Hassel, D., Cheng, P., White, M. P., Ivey, K. N., Kroll, J., Augustin, H. G., Katus, H. A., Stainier, D. Y., Srivastava, D. 2012; 111 (11): 1421-33


    Formation and remodeling of the vasculature during development and disease involve a highly conserved and precisely regulated network of attractants and repellants. Various signaling pathways control the behavior of endothelial cells, but their posttranscriptional dose titration by microRNAs is poorly understood.To identify microRNAs that regulate angiogenesis.We show that the highly conserved microRNA family encoding miR-10 regulates the behavior of endothelial cells during angiogenesis by positively titrating proangiogenic signaling. Knockdown of miR-10 led to premature truncation of intersegmental vessel growth in the trunk of zebrafish larvae, whereas overexpression of miR-10 promoted angiogenic behavior in zebrafish and cultured human umbilical venous endothelial cells. We found that miR-10 functions, in part, by directly regulating the level of fms-related tyrosine kinase 1 (FLT1), a cell-surface protein that sequesters vascular endothelial growth factor, and its soluble splice variant sFLT1. The increase in FLT1/sFLT1 protein levels upon miR-10 knockdown in zebrafish and in human umbilical venous endothelial cells inhibited the angiogenic behavior of endothelial cells largely by antagonizing vascular endothelial growth factor receptor 2 signaling.Our study provides insights into how FLT1 and vascular endothelial growth factor receptor 2 signaling is titrated in a microRNA-mediated manner and establishes miR-10 as a potential new target for the selective modulation of angiogenesis.

    View details for DOI 10.1161/CIRCRESAHA.112.279711

    View details for PubMedID 22955733

    View details for PubMedCentralID PMC3525481

  • Notch post-translationally regulates β-catenin protein in stem and progenitor cells. Nature cell biology Kwon, C., Cheng, P., King, I. N., Andersen, P., Shenje, L., Nigam, V., Srivastava, D. 2011; 13 (10): 1244-51


    Cellular decisions of self-renewal or differentiation arise from integration and reciprocal titration of numerous regulatory networks. Notch and Wnt/β-catenin signalling often intersect in stem and progenitor cells and regulate each other transcriptionally. The biological outcome of signalling through each pathway often depends on the context and timing as cells progress through stages of differentiation. Here, we show that membrane-bound Notch physically associates with unphosphorylated (active) β-catenin in stem and colon cancer cells and negatively regulates post-translational accumulation of active β-catenin protein. Notch-dependent regulation of β-catenin protein did not require ligand-dependent membrane cleavage of Notch or the glycogen synthase kinase-3β-dependent activity of the β-catenin destruction complex. It did, however, require the endocytic adaptor protein Numb and lysosomal activity. This study reveals a previously unrecognized function of Notch in negatively titrating active β-catenin protein levels in stem and progenitor cells.

    View details for DOI 10.1038/ncb2313

    View details for PubMedID 21841793

    View details for PubMedCentralID PMC3187850

  • Reporter-based isolation of induced pluripotent stem cell- and embryonic stem cell-derived cardiac progenitors reveals limited gene expression variance. Circulation research van Laake, L. W., Qian, L., Cheng, P., Huang, Y., Hsiao, E. C., Conklin, B. R., Srivastava, D. 2010; 107 (3): 340-7


    Induced pluripotent stem (iPS) cells can differentiate into multiple cell types, including cardiomyocytes and have tremendous potential for drug discovery and regenerative therapies. However, it is unknown how much variability exists between differentiated lineages from independent iPS cell lines and, specifically, how similar iPS cell-derived cardiomyocytes (iPS-CMs) are to embryonic stem (ES) cell-derived cardiomyocytes (ES-CMs).We investigated how much variability exists between differentiated lineages from independent iPS cell lines and how similar iPS-CMs are to ES-CMs.We generated mouse iPS cells in which expression of NKX2-5, an early cardiac transcription factor, was marked by transgenic green fluorescent protein (GFP). Isolation of iPS- and ES-derived NKX2-5-GFP(+) cardiac progenitor pools, marked by identical reporters, revealed unexpectedly high similarity in genome-wide mRNA expression levels. Furthermore, the variability between cardiac progenitors derived from independent iPS lines was minimal. The NKX2-5-GFP(+) iPS cells formed cardiomyocytes by numerous induction protocols and could survive upon transplantation into the infarcted mouse heart without formation of teratomas.Despite the line-to-line variability of gene expression in the undifferentiated state of ES and iPS cells, the variance narrows significantly in lineage-specific iPS-derived cardiac progenitors, and these progenitor cells can be isolated and used for transplantation without generation of unwanted cell types.

    View details for DOI 10.1161/CIRCRESAHA.109.215434

    View details for PubMedID 20558827

    View details for PubMedCentralID PMC2919280

  • A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate NATURE CELL BIOLOGY Kwon, C., Qian, L., Cheng, P., Nigam, V., Arnold, J., Srivastava, D. 2009; 11 (8): 951–U96


    Regulation of multipotent cardiac progenitor cell (CPC) expansion and subsequent differentiation into cardiomyocytes, smooth muscle or endothelial cells is a fundamental aspect of basic cardiovascular biology and cardiac regenerative medicine. However, the mechanisms governing these decisions remain unclear. Here, we show that Wnt/beta-catenin signalling, which promotes expansion of CPCs, is negatively regulated by Notch1-mediated control of phosphorylated beta-catenin accumulation within CPCs, and that Notch1 activity in CPCs is required for their differentiation. Notch1 positively, and beta-catenin negatively, regulated expression of the cardiac transcription factors, Isl1, Myocd and Smyd1. Surprisingly, disruption of Isl1, normally expressed transiently in CPCs before their differentiation, resulted in expansion of CPCs in vivo and in an embryonic stem (ES) cell system. Furthermore, Isl1 was required for CPC differentiation into cardiomyocyte and smooth muscle cells, but not endothelial cells. These findings reveal a regulatory network controlling CPC expansion and cell fate that involves unanticipated functions of beta-catenin, Notch1 and Isl1 that may be leveraged for regenerative approaches involving CPCs.

    View details for DOI 10.1038/ncb1906

    View details for Web of Science ID 000268593200008

    View details for PubMedID 19620969

    View details for PubMedCentralID PMC2748816

  • Evolution of an interloop disulfide bond in high-affinity antibody mimics based on fibronectin type III domain and selected by yeast surface display: Molecular convergence with single-domain camelid and shark antibodies JOURNAL OF MOLECULAR BIOLOGY Lipovsek, D., Lippow, S. M., Hackel, B. J., Gregson, M. W., Cheng, P., Kapila, A., Wittrup, K. D. 2007; 368 (4): 1024-1041


    The 10th human fibronectin type III domain ((10)Fn3) is one of several protein scaffolds used to design and select families of proteins that bind with high affinity and specificity to macromolecular targets. To date, the highest affinity (10)Fn3 variants have been selected by mRNA display of libraries generated by randomizing all three complementarity-determining region -like loops of the (10)Fn3 scaffold. The sub-nanomolar affinities of such antibody mimics have been attributed to the extremely large size of the library accessible by mRNA display (10(12) unique sequences). Here we describe the selection and affinity maturation of (10)Fn3-based antibody mimics with dissociation constants as low as 350 pM selected from significantly smaller libraries (10(7)-10(9) different sequences), which were constructed by randomizing only 14 (10)Fn3 residues. The finding that two adjacent loops in human (10)Fn3 provide a large enough variable surface area to select high-affinity antibody mimics is significant because a smaller deviation from wild-type (10)Fn3 sequence is associated with a higher stability of selected antibody mimics. Our results also demonstrate the utility of an affinity-maturation strategy that led to a 340-fold improvement in affinity by maximizing sampling of sequence space close to the original selected antibody mimic. A striking feature of the highest affinity antibody mimics selected against lysozyme is a pair of cysteines on adjacent loops, in positions 28 and 77, which are critical for the affinity of the (10)Fn3 variant for its target and are close enough to form a disulfide bond. The selection of this cysteine pair is structurally analogous to the natural evolution of disulfide bonds found in new antigen receptors of cartilaginous fish and in camelid heavy-chain variable domains. We propose that future library designs incorporating such an interloop disulfide will further facilitate the selection of high-affinity, highly stable antibody mimics from libraries accessible to phage and yeast surface display methods.

    View details for DOI 10.1016/j.jmb.2007.02.029

    View details for Web of Science ID 000246265200009

    View details for PubMedID 17382960