Zaniar Ghazizadeh

All Publications

• A deep learning phenome wide association study of the electrocardiogram. European heart journal. Digital health Hughes, J. W., Theurer, J., Vukadinovic, M., Rogers, A. J., Somani, S., Kang, G., Ghazizadeh, Z., O'Sullivan, J. W., Jain, S. S., Gomes, B., Salerno, M., Ashley, E., Zou, J. Y., Perez, M. V., Ouyang, D. 2025; 6 (4): 595-607

  Abstract

  Deep learning methods have shown impressive performance in detecting a range of diseases from electrocardiogram (ECG) waveforms, but the breadth of diseases that can be detected with high accuracy remains unknown, and in many cases the changes to the ECG allowing these classifications are also opaque. In this study, we aim to determine the full set of cardiac and non-cardiac conditions detectable from the ECG and to understand which ECG features contribute to the disease classification.Using large datasets of ECGs and connected electronic health records from two separate medical centres, we independently trained PheWASNet, a multi-task deep learning model, to detect 1243 different disease phenotypes from the raw ECG waveform. We confirmed that the ECG can be used to detect chronic kidney disease (AUC = 0.80), cirrhosis (AUC = 0.80), and sepsis (AUC = 0.84), as well as a range of cardiac diseases, and also found new detectable conditions, including respiratory failure (AUC = 0.86), neutropenia (AUC = 0.83), and menstrual disorders (AUC = 0.84). We found that of the 37 non-cardiac strongly detectable conditions, 35 were detectable by the model output for just four diseases, suggesting that they have similar effects on the ECG. We found that high performance in some conditions including neutropenia, respiratory failure, and sepsis can be explained by linear models based on conventional measurements taken from the ECG.Our study uncovers a range of diseases detectable in the ECG, including many previously unknown phenotypes, and makes progress towards understanding ECG features that allow this detection.

  View details for DOI 10.1093/ehjdh/ztaf047

  View details for PubMedID 40703109

  View details for PubMedCentralID PMC12282379

• Engrafted nitrergic neurons derived from hPSCs improve gut dysmotility in mice. Nature Majd, H., Samuel, R. M., Cesiulis, A., Ramirez, J. T., Kalantari, A., Barber, K., Farahvashi, S., Ghazizadeh, Z., Majd, A., Chemel, A. K., Richter, M. N., Das, S., Bendrick, J. L., Keefe, M. G., Wang, J., Shiv, R. K., Bhat, S., Khoroshkin, M., Yu, J., Nowakowski, T. J., Wen, K. W., Goodarzi, H., Thapar, N., Kaltschmidt, J. A., McCann, C. J., Fattahi, F. 2025

  Abstract

  Gastrointestinal (GI) motility disorders represent a major medical challenge, with few effective therapies available. These disorders often result from dysfunction of inhibitory nitric oxide (NO)-producing motor neurons in the enteric nervous system, which are essential for regulating gut motility. Loss or dysfunction of NO neurons is linked to severe conditions, including achalasia, gastroparesis, intestinal pseudo-obstruction and chronic constipation1,2. Here we introduce a platform based on human pluripotent stem cells (hPSCs) for therapeutic development targeting GI motility disorders. Using an unbiased screen, we identified drug candidates that modulate NO neuron activity and enhance motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define developmental programs driving the specification of NO neurons and found that inhibition of platelet-derived growth factor receptors (PDGFRs) promotes their differentiation from precursors of the enteric nervous system. Transplantation of these neurons into NO-neuron-deficient mice led to robust engraftment and improved GI motility, offering a promising cell-based therapy for neurodegenerative GI disorders. These studies provide a new framework for understanding and treating enteric neuropathies.

  View details for DOI 10.1038/s41586-025-09208-3

  View details for PubMedID 40562934

  View details for PubMedCentralID 4819870

• 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

  Abstract

  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

• A dual SHOX2:GFP; MYH6:mCherry knockin hESC reporter line for derivation of human SAN-like cells. iScience Ghazizadeh, Z., Zhu, J., Fattahi, F., Tang, A., Sun, X., Amin, S., Tsai, S. Y., Khalaj, M., Zhou, T., Samuel, R. M., Zhang, T., Ortega, F. A., Gordillo, M., Moroziewicz, D., Paull, D., Noggle, S. A., Xiang, J. Z., Studer, L., Christini, D. J., Pitt, G. S., Evans, T., Chen, S. 2022; 25 (4): 104153

  Abstract

  The sinoatrial node (SAN) is the primary pacemaker of the heart. The human SAN is poorly understood due to limited primary tissue access and limitations in robust in vitro derivation methods. We developed a dual SHOX2:GFP; MYH6:mCherry knockin human embryonic stem cell (hESC) reporter line, which allows the identification and purification of SAN-like cells. Using this line, we performed several rounds of chemical screens and developed an efficient strategy to generate and purify hESC-derived SAN-like cells (hESC-SAN). The derived hESC-SAN cells display molecular and electrophysiological characteristics of bona fide nodal cells, which allowed exploration of their transcriptional profile at single-cell level. In sum, our dual reporter system facilitated an effective strategy for deriving human SAN-like cells, which can potentially be used for future disease modeling and drug discovery.

  View details for DOI 10.1016/j.isci.2022.104153

  View details for PubMedID 35434558

  View details for PubMedCentralID PMC9010642

• Relation of Cardiovascular Risk Factors to Mortality and Cardiovascular Events in Hospitalized Patients With Coronavirus Disease 2019 (from the Yale COVID-19 Cardiovascular Registry). The American journal of cardiology Pareek, M., Singh, A., Vadlamani, L., Eder, M., Pacor, J., Park, J., Ghazizadeh, Z., Heard, A., Cruz-Solbes, A. S., Nikooie, R., Gier, C., Ahmed, Z. V., Freeman, J. V., Meadows, J., Smolderen, K. G., Lampert, R., Velazquez, E. J., Ahmad, T., Desai, N. R. 2021; 146: 99-106

  Abstract

  Individuals with established cardiovascular disease or a high burden of cardiovascular risk factors may be particularly vulnerable to develop complications from coronavirus disease 2019 (COVID-19). We conducted a prospective cohort study at a tertiary care center to identify risk factors for in-hospital mortality and major adverse cardiovascular events (MACE; a composite of myocardial infarction, stroke, new acute decompensated heart failure, venous thromboembolism, ventricular or atrial arrhythmia, pericardial effusion, or aborted cardiac arrest) among consecutively hospitalized adults with COVID-19, using multivariable binary logistic regression analysis. The study population comprised 586 COVID-19 positive patients. Median age was 67 (IQR: 55 to 80) years, 47.4% were female, and 36.7% had cardiovascular disease. Considering risk factors, 60.2% had hypertension, 39.8% diabetes, and 38.6% hyperlipidemia. Eighty-two individuals (14.0%) died in-hospital, and 135 (23.0%) experienced MACE. In a model adjusted for demographic characteristics, clinical presentation, and laboratory findings, age (odds ratio [OR], 1.28 per 5 years; 95% confidence interval [CI], 1.13 to 1.45), previous ventricular arrhythmia (OR, 18.97; 95% CI, 3.68 to 97.88), use of P2Y12-inhibitors (OR, 7.91; 95% CI, 1.64 to 38.17), higher C-reactive protein (OR, 1.81: 95% CI, 1.18 to 2.78), lower albumin (OR, 0.64: 95% CI, 0.47 to 0.86), and higher troponin T (OR, 1.84; 95% CI, 1.39 to 2.46) were associated with mortality (p <0.05). After adjustment for demographics, presentation, and laboratory findings, predictors of MACE were higher respiratory rates, altered mental status, and laboratory abnormalities, including higher troponin T (p <0.05). In conclusion, poor prognostic markers among hospitalized patients with COVID-19 included older age, pre-existing cardiovascular disease, respiratory failure, altered mental status, and higher troponin T concentrations.

  View details for DOI 10.1016/j.amjcard.2021.01.029

  View details for PubMedID 33539857

  View details for PubMedCentralID PMC7849530

• Androgen Signaling Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men. Cell stem cell Samuel, R. M., Majd, H., Richter, M. N., Ghazizadeh, Z., Zekavat, S. M., Navickas, A., Ramirez, J. T., Asgharian, H., Simoneau, C. R., Bonser, L. R., Koh, K. D., Garcia-Knight, M., Tassetto, M., Sunshine, S., Farahvashi, S., Kalantari, A., Liu, W., Andino, R., Zhao, H., Natarajan, P., Erle, D. J., Ott, M., Goodarzi, H., Fattahi, F. 2020; 27 (6): 876-889.e12

  Abstract

  SARS-CoV-2 infection has led to a global health crisis, and yet our understanding of the disease and potential treatment options remains limited. The infection occurs through binding of the virus with angiotensin converting enzyme 2 (ACE2) on the cell membrane. Here, we established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC)-derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC-derived lung organoids against SARS-CoV-2 infection. Finally, clinical data on COVID-19 patients demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and that genetic variants that increase androgen levels are associated with higher disease severity. These findings offer insights on the mechanism of disproportionate disease susceptibility in men and identify antiandrogenic drugs as candidate therapeutics for COVID-19.

  View details for DOI 10.1016/j.stem.2020.11.009

  View details for PubMedID 33232663

  View details for PubMedCentralID PMC7670929

• A human embryonic stem cell reporter line for monitoring chemical-induced cardiotoxicity. Cardiovascular research Tsai, S. Y., Ghazizadeh, Z., Wang, H. J., Amin, S., Ortega, F. A., Badieyan, Z. S., Hsu, Z. T., Gordillo, M., Kumar, R., Christini, D. J., Evans, T., Chen, S. 2020; 116 (3): 658-670

  Abstract

  Human embryonic stem cells (hESCs) can be used to generate scalable numbers of cardiomyocytes (CMs) for studying cardiac biology, disease modelling, drug screens, and potentially for regenerative therapies. A fluorescence-based reporter line will significantly enhance our capacities to visualize the derivation, survival, and function of hESC-derived CMs. Our goal was to develop a reporter cell line for real-time monitoring of live hESC-derived CMs.We used CRISPR/Cas9 to knock a mCherry reporter gene into the MYH6 locus of hESC lines, H1 and H9, enabling real-time monitoring of the generation of CMs. MYH6:mCherry+ cells express atrial or ventricular markers and display a range of cardiomyocyte action potential morphologies. At 20 days of differentiation, MYH6:mCherry+ cells show features characteristic of human CMs and can be used successfully to monitor drug-induced cardiotoxicity and oleic acid-induced cardiac arrhythmia.We created two MYH6:mCherry hESC reporter lines and documented the application of these lines for disease modelling relevant to cardiomyocyte biology.

  View details for DOI 10.1093/cvr/cvz148

  View details for PubMedID 31173076

  View details for PubMedCentralID PMC7252441

• Metastable Atrial State Underlies the Primary Genetic Substrate for MYL4 Mutation-Associated Atrial Fibrillation. Circulation Ghazizadeh, Z., Kiviniemi, T., Olafsson, S., Plotnick, D., Beerens, M. E., Zhang, K., Gillon, L., Steinbaugh, M. J., Barrera, V., Sui, S. H., Werdich, A. A., Kapur, S., Eranti, A., Gunn, J., Jalkanen, J., Airaksinen, J., Kleber, A. G., Hollmén, M., MacRae, C. A. 2020; 141 (4): 301-312

  Abstract

  Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure, stroke, and increased mortality. The myocardial substrate for AF is poorly understood because of limited access to primary human tissue and mechanistic questions around existing in vitro or in vivo models.Using an MYH6:mCherry knock-in reporter line, we developed a protocol to generate and highly purify human pluripotent stem cell-derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells. We modeled human MYL4 mutants, one of the few definitive genetic causes of AF. To explore non-cell-autonomous components of AF substrate, we also created a zebrafish Myl4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations.There was evidence of increased retinoic acid signaling in both human embryonic stem cells and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins, and loss of intracellular nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide + hydrogen. To identify potentially druggable proximate mechanisms, we performed a chemical suppressor screen integrating multiple human cellular and zebrafish in vivo endpoints. This screen identified Cx43 (connexin 43) hemichannel blockade as a robust suppressor of the abnormal phenotypes in both models of MYL4 (myosin light chain 4)-related atrial cardiomyopathy. Immunofluorescence and coimmunoprecipitation studies revealed an interaction between MYL4 and Cx43 with altered localization of Cx43 hemichannels to the lateral membrane in MYL4 mutants, as well as in atrial biopsies from unselected forms of human AF. The membrane fraction from MYL4-/- human embryonic stem cell derived atrial cells demonstrated increased phospho-Cx43, which was further accentuated by retinoic acid treatment and by the presence of risk alleles at the Pitx2 locus. PKC (protein kinase C) was induced by retinoic acid, and PKC inhibition also rescued the abnormal phenotypes in the atrial cardiomyopathy models.These data establish a mechanistic link between the transcriptional, metabolic and electrical pathways previously implicated in AF substrate and suggest novel avenues for the prevention or therapy of this common arrhythmia.

  View details for DOI 10.1161/CIRCULATIONAHA.119.044268

  View details for PubMedID 31735076

• A hPSC-based platform to discover gene-environment interactions that impact human β-cell and dopamine neuron survival. Nature communications Zhou, T., Kim, T. W., Chong, C. N., Tan, L., Amin, S., Sadat Badieyan, Z., Mukherjee, S., Ghazizadeh, Z., Zeng, H., Guo, M., Crespo, M., Zhang, T., Kenyon, R., Robinson, C. L., Apostolou, E., Wang, H., Xiang, J. Z., Evans, T., Studer, L., Chen, S. 2018; 9 (1): 4815

  Abstract

  Common disorders, including diabetes and Parkinson's disease, are caused by a combination of environmental factors and genetic susceptibility. However, defining the mechanisms underlying gene-environment interactions has been challenging due to the lack of a suitable experimental platform. Using pancreatic β-like cells derived from human pluripotent stem cells (hPSCs), we discovered that a commonly used pesticide, propargite, induces pancreatic β-cell death, a pathological hallmark of diabetes. Screening a panel of diverse hPSC-derived cell types we extended this observation to a similar susceptibility in midbrain dopamine neurons, a cell type affected in Parkinson's disease. We assessed gene-environment interactions using isogenic hPSC lines for genetic variants associated with diabetes and Parkinson's disease. We found GSTT1-/- pancreatic β-like cells and dopamine neurons were both hypersensitive to propargite-induced cell death. Our study identifies an environmental chemical that contributes to human β-cell and dopamine neuron loss and validates a novel hPSC-based platform for determining gene-environment interactions.

  View details for DOI 10.1038/s41467-018-07201-1

  View details for PubMedID 30446643

  View details for PubMedCentralID PMC6240096

• Discovery of a drug candidate for GLIS3-associated diabetes. Nature communications Amin, S., Cook, B., Zhou, T., Ghazizadeh, Z., Lis, R., Zhang, T., Khalaj, M., Crespo, M., Perera, M., Xiang, J. Z., Zhu, Z., Tomishima, M., Liu, C., Naji, A., Evans, T., Huangfu, D., Chen, S. 2018; 9 (1): 2681

  Abstract

  GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic β-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3-/- β-like cells have been unsuccessful. Here, we develop a "minimal component" protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding β-like (PP2-β) cells. Using this differentiation platform, we discover that GLIS3-/- hESCs show impaired differentiation, with significant death of PP2 and PP2-β cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated β-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes β-cell death, by activating the TGFβ pathway. This study establishes an optimized directed differentiation protocol for modeling human β-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.

  View details for DOI 10.1038/s41467-018-04918-x

  View details for PubMedID 29992946

  View details for PubMedCentralID PMC6041295

• ROCKII inhibition promotes the maturation of human pancreatic beta-like cells. Nature communications Ghazizadeh, Z., Kao, D. I., Amin, S., Cook, B., Rao, S., Zhou, T., Zhang, T., Xiang, Z., Kenyon, R., Kaymakcalan, O., Liu, C., Evans, T., Chen, S. 2017; 8 (1): 298

  Abstract

  Diabetes is linked to loss of pancreatic beta-cells. Pluripotent stem cells offer a valuable source of human beta-cells for basic studies of their biology and translational applications. However, the signalling pathways that regulate beta-cell development and functional maturation are not fully understood. Here we report a high content chemical screen, revealing that H1152, a ROCK inhibitor, promotes the robust generation of insulin-expressing cells from multiple hPSC lines. The insulin expressing cells obtained after H1152 treatment show increased expression of mature beta cell markers and improved glucose stimulated insulin secretion. Moreover, the H1152-treated beta-like cells show enhanced glucose stimulated insulin secretion and increased capacity to maintain glucose homeostasis after transplantation. Conditional gene knockdown reveals that inhibition of ROCKII promotes the generation and maturation of glucose-responding cells. This study provides a strategy to promote human beta-cell maturation and identifies an unexpected role for the ROCKII pathway in the development and maturation of beta-like cells.Our incomplete understanding of how pancreatic beta cells form limits the generation of beta-like cells from human pluripotent stem cells (hPSC). Here, the authors identify a ROCKII inhibitor H1152 as increasing insulin secreting cells from hPSCs and improving beta-cell maturation on transplantation in vivo.

  View details for DOI 10.1038/s41467-017-00129-y

  View details for PubMedID 28824164

  View details for PubMedCentralID PMC5563509