Zaniar Ghazizadeh
Affiliate, Department Funds
Fellow in Medicine - Med/Cardiovascular Medicine
Bio
Zaniar completed his Internal Medicine training at Yale New Haven Hospital/Yale School of Medicine. He received his medical degree from Tehran University of Medical Sciences and spent a few years as a post-doctoral fellow at Weill Cornell Medicine and Brigham and Women’s Hospital before his residency. His research interest lies in the development of in vitro and in vivo platforms for studying heart regeneration and precision medicine. Zaniar’s work is focused on identifying the mechanisms of cardiac arrhythmias using several experimental systems ranging from genetically engineered animal models to human pluripotent stem cell derived cardiac cell types. His ultimate goal as a clinician-scientist is to utilize this framework for drug discovery and identifying new therapeutic strategies that can prevent or reverse specific arrhythmias.
Clinical Focus
- Fellow
- Cardiology
Honors & Awards
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Merit abstract award, International Society for Stem Cell Research (2020)
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Young Investigator Award, finalist, American College of Cardiology (2020)
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Louis N. and Arnold M. Katz basic research prize, finalist, American Heart Association (2019)
Professional Education
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Residency, Yale Internal Medicine Residency Program
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MD, Tehran University of Medical Sciences
Patents
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Zaniar Ghazizadeh. "United StatesStem Cell-Derived Human Schwann Cells, Methods of Making and Methods of Uses"
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Zaniar Ghazizadeh. "United StatesMethods for the Diagnosis and Therapy of Atrial Fibrillation"
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Zaniar Ghazizadeh. "United StatesCompositions and methods for generation of sinoatrial node-like cells and their use in drug discovery"
All Publications
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A dual SHOX2:GFP; MYH6:mCherry knockin hESC reporter line for derivation of human SAN-like cells.
iScience
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
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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
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
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Androgen Signaling Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men.
Cell stem cell
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
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A human embryonic stem cell reporter line for monitoring chemical-induced cardiotoxicity.
Cardiovascular research
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
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Metastable Atrial State Underlies the Primary Genetic Substrate for MYL4 Mutation-Associated Atrial Fibrillation.
Circulation
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
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A hPSC-based platform to discover gene-environment interactions that impact human β-cell and dopamine neuron survival.
Nature communications
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
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Discovery of a drug candidate for GLIS3-associated diabetes.
Nature communications
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
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ROCKII inhibition promotes the maturation of human pancreatic beta-like cells.
Nature communications
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