Integrating cardiovascular genetics and precision medicine in clinical cardiology

Cardiology and Internal Medicine: I am a cardiologist and internal medicine physician trained at Duke University and Stanford University Hospitals. As a cardiology fellow I have received advanced training in managing complex cardiovascular disease across the CV spectrum including lipid disorders, coronary artery disease, ischemic cardiomyopathy, nonischemic cardiomyopathy, hypertension, valvular disease, arrhythmias, and infiltrative disease including cardiac amyloid and sarcoidosis. I am trained in echocardiography (level 2 board certified), catheterization, and other imaging modalities.

Stanford Center for Inherited Cardiovascular Disease (SCICD): As a clinical fellow I worked directly with Dr. Euan Ashley for 4 years where I developed expertise in treating those with inherited cardiovascular disorders. The Stanford Center for Inherited Cardiovascular Disease (SCICD) is Stanford's home to all patients with inherited CV disorders throughout the 5 major categories with inherited CV disease — those being cardiomyopathies, channelopathies, inherited lipid disorders, neuromuscular disorders with muscular dystrophies, and vascular disorders with aortopathies. In my clinical training with Dr. Ashley, I focused on those patients with cardiomyopathies, channelopathies and other inherited arrhythmogenic cardiomyopathies, and muscular dystrophies with cardiac involvement. My independent clinic within SCICD is within the heart failure program and I manage patients prior to advanced heart failure therapies such as heart transplant or mechanical circulatory support. Within cardiomyopathies, I see a mixture of patients with hypertrophic cardiomyopathies, dilated cardiomyopathies, arrhythmogenic right ventricular cardiomyopathies, as well as LV noncompaction. Within each of these cardiomyopathies, I see a spectrum of genetic underpinnings, in a clinic that is fully integrated with a team of genetic counselors where we are collecting samples and sending for genetic sequencing along with family counseling and planning during our visits. Publications from this clinical work include:

Weldy, C. S. & Ashley, E. A. Towards precision medicine in heart failure. Nat Rev Cardiol 1–18 (2021) doi:10.1038/s41569-021-00566-9.

Weldy, C. S. & Ashley, E. A. Mulibrey Nanism and the Real Time Use of Genome and Biobank Engines to Inform Clinical Care in an Ultrarare Disease. Circulation Genom Precis Medicine CIRCGEN121003430 (2021) doi:10.1161/circgen.121.003430.

Weldy, C. S., Murtha, R. & Kim, J. B. Dissecting the Genomics of Spontaneous Coronary Artery Dissection. Circulation Genom Precis Medicine 101161CIRCGEN122003867 (2022) doi:10.1161/circgen.122.003867.

Epigenetic and genetic mechanisms of cardiovascular disease

Cardiology Research Fellowship, Department of Medicine, Division of Cardiology, Stanford University School of Medicine, June 2021 – June 2023. Advisor: Dr. Thomas Quertermous, M.D.

As a physician-scientist in the lab of Dr. Quertermous I work to understand the genetic basis of cardiovascular disease and the transcriptional and epigenomic mechanisms of atherosclerosis. My work is focused across four main areas of cardiovascular genetics and mechanisms of coronary artery disease and smooth muscle biology:

Vascular smooth muscle specific ADAR1 mediated RNA editing of double stranded RNA and activation of the double stranded RNA receptor MDA5 in coronary artery disease and vascular calcification

Defining on single cell resolution the cellular and epigenomic features of human vascular disease across vascular beds of differing embryonic origin

CRISPRi screening with targeted perturb seq (TAPseq) to identify novel CAD genes in human coronary artery smooth muscle cells

Investigation of the epigenetic and molecular basis of coronary artery disease and smooth muscle cell transition in mice with conditional smooth muscle genetic deletion of CAD genes Pdgfd and Sox9

My work with Dr. Quertermous is focused on discovery of causal mechanisms of disease through leveraging human genetics with sophisticated molecular biology, single cell sequencing technologies, and mouse models of disease. This work attempts to apply multiple scientific research arms to ultimately lead to novel understandings of vascular disease and discover important new therapeutic approaches for drug discovery.

RNA editing and vascular disease — Through a collaboration with Dr. Billy Jin Li, Associate Professor of Genetics, Stanford University, I have undertaken work focused on understanding the mechanisms underpinning the human genetics link between RNA editing by adenosine deaminase acting on RNA (ADAR1) and coronary artery disease. Rare loss of function variants in ADAR1 cause a profound interferonopathy (i.e. Aicardi Goutières Syndrome and Singleton Merton Syndrome) which includes severe early onset vascular calcification. Common genetic variants which decrease RNA editing increase risk of numerous inflammatory disorders, including coronary artery disease. My work has revealed that ADAR1 is the master regulator of RNA editing in human coronary artery smooth muscle cells and I have delineated a mechanism where loss of ADAR1 RNA editing results in activation of the double strand RNA receptor MDA5 (encoded by IFIH1). Loss of RNA editing by ADAR1 regulates human SMC phenotypic transition, response to TGFβ  stimulation, and calcification, effects which can be blocked with concurrent KD of MDA5 (IFIH1), highlighting the link between ADAR1-dsRNA-MDA5 in regulating SMC phenotype. I have generated a tamoxifen inducible SMC specific Adar1 deletion mouse model which has revealed that Adar1 is required to maintain vascular integrity, where loss of Adar1 causes intravascular hemorrhage, elastin disarray, and inflammatory cell infiltrate. By leveraging human genetics with my collaborators with Dr. Li, we have the ability to predict patient RNA editing efficiency through an ‘editing-QTL polygenic risk score’ where we feel that inhibition of MDA5 can serve a valuable therapeutic strategy through a true precision medicine approach. This work has served as the basis for my K08 and AHA CDA applications, where I will 1) determine the effect of SMC specific Adar1 haploinsufficiency on progression of atherosclerosis and will identify the potential for MDA5 inhibition as therapy through investigating the effect of constitutive Ifih1-/- deletion, 2) further determine the role of ADAR1 RNA editing in human coronary artery SMCs phenotypic transition and calcification and determine specific dsRNA structures elucidating these effects, and 3) map the downstream regulatory networks of MDA5 activation through a large CRISPRi screen and computational topic modeling (cNMF) using dCas9-hTert Human Coronary Artery SMCs targeting the ~2500 genes I have identified which are regulated by RNA editing and MDA5 activation.

Grant funding received for this work:

Mentored Clinical Scientist Research Career Development Award (K08)(NIH/NHLBI, 1 K08 HL167699-01), Submitted June, 2022. PI: Weldy, Chad

Title of proposal: “ADAR Mediated RNA editing is a causal mechanism in coronary artery disease”.

Pending 08/01/2023 Start date

$850,000 over 5 years

Career Development Award, American Heart Association (AHA CDA)(23CDA1042900), July, 2023 – June, 2026. PI: Weldy, Chad

Title of proposal: “Linking RNA editing to coronary artery calcification and disease”

Activation on 07/01/2023

$231,000 over three years

NIH Loan Repayment Program (LRP) Award (NIH/NHLBI) Renewal Award, July, 2023. PI: Weldy, Chad

Title of proposal: “RNA editing is a causal mechanism of coronary artery disease”

Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship (F32) (NIH/NHLBI, 1 F32 HL160067-01), July, 2021. PI: Weldy, Chad

 Titled, “A transcriptional network which governs smooth muscle transition is mediated by causal coronary artery disease gene PDGFD”

*Received perfect score with impact score 10, 1st percentile

NIH Loan Repayment Program (LRP) Award (NIH/NHLBI), July, 2021. PI: Weldy, Chad

Title of proposal: "Single cell transcriptomic and epigenomic features of human atherosclerosis".

This will award up to $100,000 towards student loans over the next 24 months with opportunity for renewal after 24 months. 

Residency Research, Department of Pediatrics, Division of Cardiology, Stanford University School of Medicine, September 2017 – 2020. Advisor: Dr. Sushma Reddy, M.D.

During internal medicine residency, I developed a project with Dr. Sushma Reddy (Pediatric Cardiology) investigating peripheral blood global microRNA expression profiles as a biomarker of progressive right ventricular (RV) dysfunction in adult patients with tetralogy of Fallot. By utilizing microarray and RNAseq technologies in adult patients with TOF and varying degrees of RV dysfunction, our work led to the discovery that as RV failure progresses, peripheral blood miRNA expression dynamically changes and reflects the degree of RV dysfunction. Pathway analyses further suggest that dysregulated miRNA reflect changes in cell cycle progression, angiogenesis, fibrosis, and fatty acid metabolism, potentially identifying unique mechanisms of disease in mediating RV failure in adults with TOF (Weldy et al., PLoS ONE, 2020).

Postdoctoral Fellowship, Department of Medicine, Division of Cardiology, University of Washington, June 2012 – June 2014. Fellowship advisor: Dr. Michael T. Chin, M.D., Ph.D.

During my postdoctoral fellowship, I worked under Dr. Michael T. Chin within the UW Division of Cardiology where I investigated the fetal origins of adult cardiovascular disease. My work led to the discovery that in utero and early life exposure to diesel exhaust air pollution increases adult susceptibility to heart failure in mice. By inducing heart failure in mice using the transverse aortic constriction model, we observed that mice exposed to diesel exhaust during in utero and early life development develop a pronounced dilated cardiomyopathy, systolic dysfunction, and extensive myocardial fibrosis that exceeds that found in control mice (Weldy et al. Particle and Fibre Toxicology, 2013). In addition, we have shown that in utero exposure to diesel exhaust directly impacts the placenta, promoting reduced placental weight and increased placental inflammation and vascular oxidative stress. We have found this effect on in utero development is sufficient to cause increased body weight, altered blood pressure, and increased susceptibility to heart failure in adult male offspring (Weldy et al. PloS One, 2014). We believe that air pollution alters placental function and embryonic development in a manner that confers epigenetic reprogramming that may determine one's risk of cardiovascular disease throughout life, and we have discovered that this in utero exposure can lead to DNA methylation changes in specific genes, including Mir133a2 (Goodson and Weldy, FASEB J, 2017). We are utilizing next generation bisulfite sequencing to investigate the DNA methylome to further investigate potential epigenetic determinants of this hypersensitivity. As I believe these environmental exposures have developmental effects that program our adult susceptibility to disease, it is my goal to understand what fetal programming occurs, determine if there may be markers of this programming, and develop clinical therapeutics that would allow intervention prior to disease onset.

PhD, Program in Toxicology, Department of Environmental and Occupational Health, School of Public Health, University of Washington, June 2007 – June 2012, Graduate Research Assistant. Advisor: Dr. Terrance Kavanagh, Ph.D.

In my Ph.D. work, I joined the lab of Dr. Terrance J. Kavanagh to investigate the role of oxidative stress and biosynthesis of the antioxidant glutathione (GSH) in mediating vascular function and pulmonary inflammation in response to toxic injury. Our work led to mechanistic discoveries that help us understand how GSH mediates vascular reactivity and nitric oxide bioavailability and how injury from inhalation of air pollution can elicit systemic vascular effects. My dissertation identified key interactions between macrophages and vascular endothelium following diesel exhaust (DE) particulate exposure (Weldy et al., Toxicology in Vitro, 2011), discovered that heterozygosity in a GSH synthesis gene increases susceptibility to DE-induced lung inflammation (Weldy et al., Inhalation Toxicology, 2011), delineated the role for GSH in mediating vascular reactivity and nitric oxide production (Weldy et al., Free Radical Biology and Medicine, 2012), and further identified the gene-environment interaction between GSH synthesis and DE exposure on vascular function (Weldy et al., Inhalation Toxicology, 2013). As air pollution and exposure to fine ambient particulate matter (PM2.5) is a major cause of cardiovascular disease worldwide, these investigations have led to our better basic understanding of particle toxicology and the role of oxidative stress and the genetic determinants of antioxidant synthesis in mediating vascular function in response to injury.

Publications

Shi H, Nguyen T, Zhao Q, Cheng P, Sharma D, Kim H-J, Kim JB, Wirka R, Weldy CS, Monteiro JP, Quertermous T. Discovery of Transacting Long Noncoding RNAs That Regulate Smooth Muscle Cell Phenotype. Circ Res. 2023;

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

Navarre, B. M., Clouthier, K. L., Ji, X., Taylor, A., Weldy, C. S., Dubin, A., Reddy, S. miR Profile of Chronic Right Ventricular Pacing: a Pilot Study in Children with Congenital Complete Atrioventricular Block. J Cardiovasc Transl 1–13 (2022) doi:10.1007/s12265-022-10318-w.

Weldy, C. S., Murtha, R. & Kim, J. B. Dissecting the Genomics of Spontaneous Coronary Artery Dissection. Circulation Genom Precis Medicine 101161CIRCGEN122003867 (2022) doi:10.1161/circgen.122.003867.

Weldy, C. S. & Ashley, E. A. Towards precision medicine in heart failure. Nat Rev Cardiol 1–18 (2021) doi:10.1038/s41569-021-00566-9.

Featured on the cover of the November 2021 edition of Nature Reviews Cardiology

Weldy, C. S. & Ashley, E. A. Mulibrey Nanism and the Real Time Use of Genome and Biobank Engines to Inform Clinical Care in an Ultrarare Disease. Circulation Genom Precis Medicine CIRCGEN121003430 (2021) doi:10.1161/circgen.121.003430.

Weldy, C., Syed, S., Amsallem, M., Hu, D., Ji, X., Punn, R., Taylor, A., Navarre, B., Reddy, S. (2020). Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot. PLOS ONE 15(11), e0241476. https://dx.doi.org/10.1371/journal.pone.0241476

Featured in Stanford University School of Medicine SCOPE blog — “Tiny bits of RNA give window into adult congenital heart disease” https://scopeblog.stanford.edu/2020/11/16/tiny-bits-of-rna-give-window-into-adult-congenital-heart-disease-in-stanford-study/

Goodson, J.M., Weldy, C.S., MacDonald, J.W., Liu, Y, Bammler, T.K., Chien, W-M and Chin, M.T. (2017). In utero exposure to diesel exhaust particulates is associated with an altered cardiac transcriptional response to transverse aortic constriction and altered DNA methylation. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2017:fj.201700032R.

Liu, Y., Weldy, C. S., & Chin, M. T. (2016). Neonatal Diesel Exhaust Particulate Exposure Does Not Predispose Mice to Adult Cardiac Hypertrophy or Heart Failure. International Journal of Environmental Research and Public Health, 13(12), 1178. http://doi.org/10.3390/ijerph13121178

Hartman, M. E., Liu, Y., Zhu, W.-Z., Chien, W.-M., Weldy, C. S., Fishman, G. I., et al. (2014). Myocardial deletion of transcription factor CHF1/Hey2 results in altered myocyte action potential and mild conduction system expansion but does not alter conduction system function or promote spontaneous arrhythmias. The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 28(7), 3007–3015. http://doi.org/10.1096/fj.14-251728

Weldy, C. S., Liu, Y., Liggitt, H. D., & Chin, M. T. (2014). In Utero Exposure to Diesel Exhaust Air Pollution Promotes Adverse Intrauterine Conditions, Resulting in Weight Gain, Altered Blood Pressure, and Increased Susceptibility to Heart Failure in Adult Mice. PloS One, 9(2), e88582. http://doi.org/10.1371/journal.pone.0088582

Weldy, C. S., Liu, Y., Chang, Y.-C., Medvedev, I. O., Fox, J. R., Larson, T. V., et al. (2013). In utero and early life exposure to diesel exhaust air pollution increases adult susceptibility to heart failure in mice. Particle and Fibre Toxicology, 10(1), 59. http://doi.org/10.1186/1743-8977-10-59

Society of Toxicology, Inhalation and Respiratory Specialty Section, 2014 National Paper of the Year Award

Liu, Y., Chien, W.-M., Medvedev, I. O., Weldy, C. S., Luchtel, D. L., Rosenfeld, M. E., & Chin, M. T. (2013). Inhalation of diesel exhaust does not exacerbate cardiac hypertrophy or heart failure in two mouse models of cardiac hypertrophy. Particle and Fibre Toxicology, 10(1), 49. http://doi.org/10.1186/1743-8977-10-49

Weldy, C. S., Luttrell, I. P., White, C. C., Morgan-Stevenson, V., Cox, D. P., Carosino, C. M., et al. (2013). Glutathione (GSH) and the GSH synthesis gene Gclm modulate plasma redox and vascular responses to acute diesel exhaust inhalation in mice. Inhalation Toxicology, 25(8), 444–454. http://doi.org/10.3109/08958378.2013.801004

McConnachie, L. A., Botta, D., White, C. C., Weldy, C. S., Wilkerson, H.-W., Yu, J., et al. (2013). The Glutathione Synthesis Gene Gclm Modulates Amphiphilic Polymer-Coated CdSe/ZnS Quantum Dot-Induced Lung Inflammation in Mice. PloS One, 8(5), e64165. http://doi.org/10.1371/journal.pone.0064165

Weldy, C. S., Luttrell, I. P., White, C. C., Morgan-Stevenson, V., Bammler, T. K., Beyer, R. P., et al. (2012). Glutathione (GSH) and the GSH synthesis gene Gclm modulate vascular reactivity in mice. Free Radical Biology and Medicine, 53(6), 1264–1278. http://doi.org/10.1016/j.freeradbiomed.2012.07.006

Weldy, C. S., White, C. C., Wilkerson, H.-W., Larson, T. V., Stewart, J. A., Gill, S. E., et al. (2011). Heterozygosity in the glutathione synthesis gene Gclm increases sensitivity to diesel exhaust particulate induced lung inflammation in mice. Inhalation Toxicology, 23(12), 724–735. http://doi.org/10.3109/08958378.2011.608095

Weldy, C. S., Wilkerson, H.-W., Larson, T. V., Stewart, J. A., & Kavanagh, T. J. (2011). DIESEL particulate exposed macrophages alter endothelial cell expression of eNOS, iNOS, MCP1, and glutathione synthesis genes. Toxicology in Vitro : an International Journal Published in Association with BIBRA, 25(8), 2064–2073. http://doi.org/10.1016/j.tiv.2011.08.008

Weldy, C. S., & Huesemann, M. H. (2007). Lipid Production by Dunaliella salina in Batch Culture: Effects of Nitrogen Limitation and Light Intensity. Journal of Undergraduate Research, VII:115-122, 7.

Submitted/Preprint

Weldy CS, Cheng PP, Pedroza AJ, Dalal AR, Sharma D, Kim H-J, Shi H, Nguyen T, Kundu RK, Fischbein MP and Quertermous T. The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci. bioRxiv. 2022:2022.05.18.492517.