Publications by authors named "Juyong B Kim"

10 Publications

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Immunologic effects of forest fire exposure show increases in IL-1β and CRP.

Allergy 2020 09 16;75(9):2356-2358. Epub 2020 Apr 16.

Sean N Parker Center for Allergy and Asthma Research, Stanford University, Stanford, CA, USA.

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http://dx.doi.org/10.1111/all.14251DOI Listing
September 2020

Utility of High-Sensitivity and Conventional Troponin in Patients Undergoing Transcatheter Aortic Valve Replacement: Incremental Prognostic Value to B-type Natriuretic Peptide.

Sci Rep 2019 10 17;9(1):14936. Epub 2019 Oct 17.

Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States.

High-sensitivity Troponin (hs-Tn) has emerged as a useful marker for patients with myocardial injury or heart failure. However, few studies have compared intermediate and hs-Tn in patients undergoing transcatheter aortic valve replacement (TAVR). Moreover, there remains uncertainty of which thresholds are the most useful for discriminating ventricular dysfunction or outcome. In this study we prospectively enrolled 105 patients with severe aortic stenosis (AS) who underwent TAVR as well as blood sampling for high-sensitivity (hs-TnI) and conventional troponin I (EXL-LOCI and RXL) assessment. Patients underwent comprehensive pre-procedure echocardiography. Ventricular dysfunction was defined using left ventricular mass index (LVMI), LV global longitudinal strain (LVGLS) and LV end-diastolic pressure. The mean age was 84.0 ± 8.7 years old and 60% were male sex with mean transaortic pressure gradient of 50.1 ± 16.0 mmHg and AVA of 0.63 ± 0.19 cm. When using a threshold of 6 ng/L, 77% had positive hs-TnI while 27% had positive hs-TnI using recommended thresholds (16 ng/L for female and 34 ng/L for male). Troponin levels were higher in the presence of abnormal LV phenotypes. The strongest correlate of troponin was LVMI. During median follow-up of 375 days, 21 patients (20%) died. Lower threshold of hs-TnI and EXL-TnI was more discriminatory for overall mortality (Log-rank P = 0.03 for both), while higher threshold of hs-TnI (p = 0.75) and RXL-TnI were not (p = 0.30). Combining hs-TnI and BNP improved to predict long-term outcome (p = 0.004). In conclusion, hs-TnI levels correlated with the degree of LV dysfunction phenotypes. Furthermore, applying a lower threshold for hs-TnI performed better for outcome prediction than a recommended threshold in patients undergoing TAVR. Combining hs-TnI with BNP helped better risk stratification.
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http://dx.doi.org/10.1038/s41598-019-51371-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797771PMC
October 2019

Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis.

Nat Med 2019 08 29;25(8):1280-1289. Epub 2019 Jul 29.

Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.

In response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed 'fibromyocytes', rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21-a causal CAD gene-markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.
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http://dx.doi.org/10.1038/s41591-019-0512-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274198PMC
August 2019

Incremental Value of Deformation Imaging and Hemodynamics Following Heart Transplantation: Insights From Graft Function Profiling.

JACC Heart Fail 2017 12;5(12):930-939

Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford, California; Stanford Cardiovascular Institute, Stanford, California. Electronic address:

Objectives: This study investigated to define graft dysfunction and to determine its incremental association with long-term outcome after heart transplantation (HT).

Background: Although graft failure is an established cause of late mortality after HT, few studies have analyzed the prognostic value of graft dysfunction at 1- and 5-year follow-up of HT.

Methods: Patients who underwent HT and completed their first annual evaluation with right heart catheterization and echocardiography at Stanford University between January 1999 and December 2011 were included in the study. Hierarchical clustering was used to identify modules to capture independent features of graft dysfunction at 1 year. The primary endpoint for analysis consisted of the composite of cardiovascular mortality, re-transplantation, or heart failure hospitalization within 5 years of HT. The study further explored whether changes in graft dysfunction between 1 and 5 years were associated with 10-year all-cause mortality.

Results: A total of 215 HT recipients were included in the study. Using hierarchical clustering, 3 functional modules were identified; among them, left ventricular global longitudinal strain (LVGLS), stroke volume index, and right atrial pressure (RAP) or pulmonary capillary wedge pressure (PCWP) captured key features of graft function. Graft dysfunction based on pre defined LVGLS in absolute value <14%, stroke volume index <35 ml/m, RAP >10 mm Hg, or PCWP >15 mm Hg were present in 41%, 36%, and 27%, respectively. The primary endpoint at 5 years occurred in 52 patients (24%), whereas 10-year all-cause mortality occurred in 30 (27%) of 110 patients alive at 5 years. On multivariate analysis, RAP (standardized hazard ratio: 1.63), LVGLS (standardized hazard ratio: 1.39), and a history of hemodynamically compromising rejection within 1 year (hazard ratio: 2.18) were independent predictors of 5-year outcome. RAP at 5 years, as well as change in RAP from 1 to 5 years, was predictive of 10-year all-cause mortality.

Conclusions: RAP and LVGLS at the first annual evaluation provide complementary prognostic information in predicting 5-year outcome after HT.
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http://dx.doi.org/10.1016/j.jchf.2017.10.011DOI Listing
December 2017

Dynamic changes in aortic impedance after transcatheter aortic valve replacement and its impact on exploratory outcome.

Int J Cardiovasc Imaging 2017 Nov 17;33(11):1693-1701. Epub 2017 May 17.

Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive Room H2103, Stanford, CA, 94305, USA.

Valvulo-arterial impedance (Zva) has been shown to predict worse outcome in medically managed aortic stenosis (AS) patients. We aimed to investigate the association between Zva and left ventricular (LV) adaptation and to explore the predictive value of Zva for cardiac functional recovery and outcome after transcatheter aortic valve replacement (TAVR). We prospectively enrolled 128 patients with AS who underwent TAVR. Zva was calculated as: (systolic blood pressure + mean transaortic gradient)/stroke volume index). Echocardiographic assessment occurred at baseline, 1-month and 1-year after TAVR. The primary endpoints were to investigate associations between Zva and global longitudinal strain (GLS) at baseline as well as GLS change after TAVR. The secondary was to compare all-cause mortality after TAVR between patients with pre-defined Zva (=5 mmHg m/ml), stroke volume index (=35 ml/m), and GLS (=-15%) cutoffs. The mean GLS was reduced (-13.0 ± 3.2%). The mean Zva was 5.2 ± 1.6 mmHg*m/ml with 55% of values ≥5.0 mmHg*m/ml, considered to be abnormally high. Higher Zva correlated with worse GLS (r = -0.33, p < 0.001). After TAVR, Zva decreased significantly (5.1 ± 1.6 vs. 4.5 ± 1.6 mmHg*m/ml, p = 0.001). A reduction of Zva at 1-month was associated with GLS improvement at 1-month (r = -0.31, p = 0.001) and at 1-year (r = -0.36 and p = 0.001). By Kaplan-Meier analysis, patients with higher Zva at baseline had higher mortality (Log-rank p = 0.046), while stroke volume index and GLS did not differentiate outcome (Log-rank p = 0.09 and 0.25, respectively). As a conclusion, Zva is correlated with GLS in AS as well as GLS improvement after TAVR. Furthermore, a high baseline Zva may have an additional impact to traditional parameters on predicting worse mortality after TAVR.
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http://dx.doi.org/10.1007/s10554-017-1155-6DOI Listing
November 2017

Genetics and Genomics of Coronary Artery Disease.

Curr Cardiol Rep 2016 10;18(10):102

Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305-5233, USA.

Coronary artery disease (or coronary heart disease), is the leading cause of mortality in many of the developing as well as the developed countries of the world. Cholesterol-enriched plaques in the heart's blood vessels combined with inflammation lead to the lesion expansion, narrowing of blood vessels, reduced blood flow, and may subsequently cause lesion rupture and a heart attack. Even though several environmental risk factors have been established, such as high LDL-cholesterol, diabetes, and high blood pressure, the underlying genetic composition may substantially modify the disease risk; hence, genome composition and gene-environment interactions may be critical for disease progression. Ongoing scientific efforts have seen substantial advancements related to the fields of genetics and genomics, with the major breakthroughs yet to come. As genomics is the most rapidly advancing field in the life sciences, it is important to present a comprehensive overview of current efforts. Here, we present a summary of various genetic and genomics assays and approaches applied to coronary artery disease research.
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http://dx.doi.org/10.1007/s11886-016-0777-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872834PMC
October 2016

Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci.

Nat Commun 2016 07 8;7:12092. Epub 2016 Jul 8.

Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.

Coronary artery disease (CAD) is the leading cause of mortality and morbidity, driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies have identified >150 loci associated with CAD and myocardial infarction susceptibility in humans. A majority of these variants reside in non-coding regions and are co-inherited with hundreds of candidate regulatory variants, presenting a challenge to elucidate their functions. Herein, we use integrative genomic, epigenomic and transcriptomic profiling of perturbed human coronary artery smooth muscle cells and tissues to begin to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps, we prioritize 64 candidate variants and perform allele-specific binding and expression analyses at seven top candidate loci: 9p21.3, SMAD3, PDGFD, IL6R, BMP1, CCDC97/TGFB1 and LMOD1. We validate our findings in expression quantitative trait loci cohorts, which together reveal new links between CAD associations and regulatory function in the appropriate disease context.
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http://dx.doi.org/10.1038/ncomms12092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941121PMC
July 2016

Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells That Contribute to the Fibrous Cap.

PLoS Genet 2015 May 28;11(5):e1005155. Epub 2015 May 28.

Department of Medicine, Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, California, United States of America.

Recent genome wide association studies have identified a number of genes that contribute to the risk for coronary heart disease. One such gene, TCF21, encodes a basic-helix-loop-helix transcription factor believed to serve a critical role in the development of epicardial progenitor cells that give rise to coronary artery smooth muscle cells (SMC) and cardiac fibroblasts. Using reporter gene and immunolocalization studies with mouse and human tissues we have found that vascular TCF21 expression in the adult is restricted primarily to adventitial cells associated with coronary arteries and also medial SMC in the proximal aorta of mouse. Genome wide RNA-Seq studies in human coronary artery SMC (HCASMC) with siRNA knockdown found a number of putative TCF21 downstream pathways identified by enrichment of terms related to CAD, including "vascular disease," "disorder of artery," and "occlusion of artery," as well as disease-related cellular functions including "cellular movement" and "cellular growth and proliferation." In vitro studies in HCASMC demonstrated that TCF21 expression promotes proliferation and migration and inhibits SMC lineage marker expression. Detailed in situ expression studies with reporter gene and lineage tracing revealed that vascular wall cells expressing Tcf21 before disease initiation migrate into vascular lesions of ApoE-/- and Ldlr-/- mice. While Tcf21 lineage traced cells are distributed throughout the early lesions, in mature lesions they contribute to the formation of a subcapsular layer of cells, and others become associated with the fibrous cap. The lineage traced fibrous cap cells activate expression of SMC markers and growth factor receptor genes. Taken together, these data suggest that TCF21 may have a role regulating the differentiation state of SMC precursor cells that migrate into vascular lesions and contribute to the fibrous cap and more broadly, in view of the association of this gene with human CAD, provide evidence that these processes may be a mechanism for CAD risk attributable to the vascular wall.
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http://dx.doi.org/10.1371/journal.pgen.1005155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447275PMC
May 2015

Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci.

PLoS Genet 2015 May 28;11(5):e1005202. Epub 2015 May 28.

Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America.

To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.
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http://dx.doi.org/10.1371/journal.pgen.1005202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447360PMC
May 2015

The effect of transvenous pacemaker and implantable cardioverter defibrillator lead placement on tricuspid valve function: an observational study.

J Am Soc Echocardiogr 2008 Mar 2;21(3):284-7. Epub 2007 Jul 2.

Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York, USA.

This study assessed the effect of transtricuspid placement of permanent pacemaker (PPM) and implantable cardioverter defibrillator (ICD) leads on tricuspid regurgitation (TR) in 248 patients with echocardiograms before and after placement. Some 21.2% of patients with baseline mild TR or less developed abnormal TR (3.4% mild-moderate, 12.8% moderate, 1.1% moderate-severe, 3.9% severe) after implant. TR worsened by 1 grade or more after implant in 24.2% (20.7% of PPMs vs. 32.4% of ICDs; P < .05). TR worsening was more common with ICDs than PPMs in patients with baseline mild TR or less. After lead implantation, abnormal TR developed in 21.2% and severe TR developed in 3.9% of patients with initially normal TR. TR worsened by at least 1 grade in 24.2%. Patients with ICDs had a higher rate of TR worsening compared with patients with PPMs (32.4% vs. 20.1%; P < .05).
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http://dx.doi.org/10.1016/j.echo.2007.05.022DOI Listing
March 2008
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