- Cardiovascular Disease
- Coronary Artery Disease
- Acute Coronary Syndrome
- Percutaneous Coronary Intervention
- Aortic Valve Stenosis
- Transcatheter Aortic Valve Replacement
Fellowship, Stanford University School of Medicine, General Cardiology (2015)
Fellowship, Stanford University School of Medicine, Interventional Cardiology (2014)
Residency: UCLA Medical Center Internal Medicine (2009) CA
MPH, Mailman School of Public Health, Columbia University, Health Policy (2006)
Medical Education: New York University School of Medicine (2006) NY
BS, Massachusetts Institute of Technology, ChemE/Biology (2001)
Current Research and Scholarly Interests
The lifetime risk of developing cardiovascular disease (CVD) is determined by the genetic makeup and exposure to modifiable risk factors. The Cardiovascular Link to Environmental ActioN (CLEAN) Lab is interested in understanding how various environmental pollutants (eg. tobacco, e-cigarettes, air pollution and wildfire) interact with genes to affect the transcriptome, epigenome, and eventually disease phenotype of CVD. The current focus is to investigate how different toxic exposures can adversely remodel the vascular wall leading to increased cardiac events. We intersect human genomic discoveries with animal models of disease, in-vitro and in-vivo systems of exposure, single-cell sequencing technologies to solve these questions. Additionally, we collaborate with various members of the Stanford community to develop biomarkers that will aid with detection and prognosis of CVD. We are passionate about the need to reduce the environmental effects on health through strong advocacy and outreach.
Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment (The EXACT Trial)
The primary purpose of this trial is to determine the safety of XC001 (AdVEGFXC1) in patients who suffer from angina caused by coronary artery disease and have no other treatment options. Subjects in this study will receive one of four intramyocardial doses of XC001 that expresses human vascular endothelial growth factor (VEGF) which induces therapeutic angiogenesis (revascularization).
- Dissecting the Genomics of Spontaneous Coronary Artery Dissection. Circulation. Genomic and precision medicine 2022: 101161CIRCGEN122003867
Left Ventricular Hypertrophy and Biomarkers of Cardiac Damage and Stress in Aortic Stenosis.
Journal of the American Heart Association
Background Left ventricular hypertrophy (LVH) is associated with increased mortality risk and rehospitalization after transcatheter aortic valve replacement among those with severe aortic stenosis. Whether cardiac troponin (cTnT) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) risk stratify patients with aortic stenosis and without LVH is unknown. Methods and Results In a multicenter prospective registry of 923 patients with severe aortic stenosis undergoing transcatheter aortic valve replacement, we included 674 with core-laboratory-measured LV mass index, cTnT, and NT-proBNP. LVH was defined by sex-specific guideline cut-offs and elevated biomarker levels were based on age and sex cut-offs. Adjusted Cox proportional hazards models evaluated associations between LVH and biomarkers and all-cause death out to 5years. Elevated cTnT and NT-proBNP were present in 82% and 86% of patients with moderate/severe LVH, respectively, as compared with 66% and 69% of patients with no/mild LVH, respectively (P<0.001 for each). After adjustment, compared with no/mild LVH, moderate/severe LVH was associated with an increased hazard of mortality (adjusted hazard ratio [aHR], 1.34; 95% CI 1.01-1.77, P=0.043). cTnT and NT-proBNP each risk stratified patients with moderate/severe LVH (P<0.05). In a model with both biomarkers and LVH included, elevated cTnT (aHR, 2.08; 95% CI 1.45-3.00, P<0.001) and elevated NT-proBNP (aHR, 1.46; 95% CI 1.00-2.11, P=0.049) were each associated with increased mortality risk, whereas moderate/severe LVH was not (P=0.15). Conclusions Elevations in circulating cTnT and NT-proBNP are more common as LVH becomes more pronounced but are also observed in those with no/minimal LVH. As measures of maladaptive remodeling and cardiac injury, cTnT and NT-proBNP predict post-transcatheter aortic valve replacement mortality better than LV mass index. These findings may have important implications for risk stratification and treatment of patients with aortic stenosis.
View details for DOI 10.1161/JAHA.121.023466
View details for PubMedID 35301869
Inter-racial differences in patients undergoing transcatheter aortic valve implantation.
Heart (British Cardiac Society)
OBJECTIVE: Little information exists about inter-racial differences in patients with aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). We investigated whether differences in baseline characteristics between Asian and non-Asian population may contribute to disparities in clinical outcomes after TAVI.METHODS: We performed a registry-based, multinational cohort study of patients with severe AS who underwent TAVI at two centres in the USA and one centre in South Korea. The primary outcome was a composite of death, stroke or rehospitalisation at 1year.RESULTS: Of 1412 patients, 581 patients were Asian and 831 were non-Asian (87.5% white, 1.7% black, 6.1% Hispanic or 4.7% others). There were substantial differences in baseline characteristics between two racial groups. The primary composite outcome was significantly lower in the Asian group than in the non-Asian group (26.0% vs 35.0%; HR 0.73; 95% CI 0.59 to 0.89; p=0.003). However, after adjustment of baseline covariates, the risk of primary composite outcome was not significantly different (HR 0.79; 95%CI 0.60 to 1.03; p=0.08). The all-cause mortality at 1year was significantly lower in the Asian group than the non-Asian group (7.4% vs 12.5%; HR 0.60; 95%CI 0.41 to 0.88; p=0.009). After multivariable adjustment, the risk of all-cause mortality was also similar (HR 1.17; 95%CI 0.73 to 1.88; p=0.52).CONCLUSIONS: There were significant differences in baseline and procedural factors among Asian and non-Asian patients who underwent TAVI. Observed inter-racial differences in clinical outcomes were largely explained by baseline differences in clinical, anatomical and procedural factors.TRIAL REGISTRATION NUMBER: NCT03826264 (https://wwwclinicaltrialsgov).
View details for DOI 10.1136/heartjnl-2021-320364
View details for PubMedID 35110384
ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis
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
Distance between valvular leaflet and coronary ostium predicting risk of coronary obstruction during TAVR.
International journal of cardiology. Heart & vasculature
1800; 37: 100917
Background: The aim of this study was to evaluate the role of the distance between the aortic valve in projected position to the coronary ostium to determine risk of coronary artery obstruction after transcatheter aortic valve replacement (TAVR).Methods: An Expected Leaflet-to-ostium Distance (ELOD) was obtained on pre-TAVR planning computed tomography by subtracting leaflet thickness and the distances from the center to the annular rim at annulus level and from the center to the coronary ostium at mid-ostial level. Variables were compared between patients with and without coronary obstruction and the level of association between variables was assessed using log odds ratio (OR).Results: A total of 177 patients with 353 coronary arteries was analyzed. Mean annulus diameters (22.8±2.8mm and 23.4±1.0mm, p>0.05) and mean sinus of Valsalva (SOV) diameters (31.2±3.6mm and 31.9±3.6mm, p>0.05) were similar between patients with lower and higher coronary heights, respectively. There were three coronary obstruction cases. ELOD≤2mm in combination with leaflet length longer than mid-ostial height allowed for discrimination of cases with and without coronary obstruction. There was a significant association between coronary obstruction event and ELOD≤2mm (log OR=6.180, p<0.001).Conclusions: Our study showed that a combination of ELOD<2mm and a longer leaflet length than mid-ostial height may be associated with increased risk for coronary obstruction during TAVR.
View details for DOI 10.1016/j.ijcha.2021.100917
View details for PubMedID 34917750
Racial Differences in the Incidence and Impact of Prosthesis-Patient MismatchAfter Transcatheter AorticValve Replacement.
JACC. Cardiovascular interventions
OBJECTIVES: The aim of this study was to compare the incidence and prognostic significance of prosthesis-patient mismatch (PPM) after transcatheter aortic valve replacement (TAVR) according to racial groups.BACKGROUND: PPM after TAVR may be of more concern in Asian populations considering their relatively small annular and valve sizes compared with Western populations.METHODS: TP-TAVR (Transpacific TAVR Registry) was an international multicenter cohort study of patients with severe aortic stenosis who underwent TAVR in the United States and South Korea from January 2015 to November 2019. PPM was defined as moderate (0.65-0.85cm2/m2) or severe (<0.65cm2/m2) at the indexed effective orifice area. The primary outcome was a composite of death, stroke, or rehospitalization at 1 year.RESULTS: Among 1,101 eligible patients (533 Asian and 569 non-Asian), the incidence of PPM was significantly lower in the Asian population (33.6%; moderate, 26.5%; severe, 7.1%) than in the non-Asian population (54.5%; moderate, 29.8%; severe, 24.7%). The 1-year rate of the primary outcome was similar between the PPM and non-PPM groups (27.5% vs 28.1%; P=0.69); this pattern was consistent between Asian (25.4% vs 25.2%; P=0.31) and non-Asian (28.7% vs 32.1%; P=0.97) patients. After multivariable adjustment, the risk for the primary outcome did not significantly differ between the PPM and non-PPM groups in the overall population (HR: 0.95; 95% CI: 0.74-1.21), in Asian patients (HR: 1.07; 95%CI: 0.74-1.55), and in non-Asian patients (HR: 0.86; 95%CI: 0.63-1.19).CONCLUSIONS: In this study of patients with severe aortic stenosis who underwent TAVR, the incidence of PPM was significantly lower in Asian patients than in non-Asian patients. The 1-year risk for the primary composite outcome was similar between the PPM and non-PPM groups regardless of racial group. (Transpacific TAVR Registry [TP-TAVR]; NCT03826264).
View details for DOI 10.1016/j.jcin.2021.08.038
View details for PubMedID 34838464
CTA pulmonary artery enlargement in patients with severe aortic stenosis: Prognostic impact after TAVR.
Journal of cardiovascular computed tomography
BACKGROUND: Identifying high-risk patients who will not derive substantial survival benefit from TAVR remains challenging. Pulmonary hypertension is a known predictor of poor outcome in patients undergoing TAVR and correlates strongly with pulmonary artery (PA) enlargement on CTA. We sought to evaluate whether PA enlargement, measured on pre-procedural computed tomography angiography (CTA), is associated with 1-year mortality in patients undergoing TAVR.METHODS: We retrospectively included 402 patients undergoing TAVR between July 2012 and March 2016. Clinical parameters, including Society of Thoracic Surgeons (STS) score and right ventricular systolic pressure (RVSP) estimated by transthoracic echocardiography were reviewed. PA dimensions were measured on pre-procedural CTAs. Association between PA enlargement and 1-year mortality was analyzed. Kaplan-Meier and Cox proportional hazards regression analyses were performed.RESULTS: The median follow-up time was 433 (interquartiles 339-797) days. A total of 56/402 (14%) patients died within 1 year after TAVR. Main PA area (area-MPA) was independently associated with 1-year mortality (hazard ratio per standard deviation equal to 2.04 [95%-confidence interval (CI) 1.48-2.76], p<0.001). Area under the curve (95%-CI) of the clinical multivariable model including STS-score and RVSP increased slightly from 0.67 (0.59-0.75) to 0.72 (0.72-0.89), p=0.346 by adding area-MPA. Although the AUC increased, differences were not significant (p=0.346). Kaplan-Meier analysis showed that mortality was significantly higher in patients with a pre-procedural non-indexed area-MPA of ≥7.40cm2 compared to patients with a smaller area-MPA (mortality 23% vs. 9%; p<0.001).CONCLUSIONS: Enlargement of MPA on pre-procedural CTA is independently associated with 1-year mortality after TAVR.
View details for DOI 10.1016/j.jcct.2021.03.004
View details for PubMedID 33795188
Immune biomarkers link air pollution exposure to blood pressure in adolescents.
Environmental health : a global access science source
2020; 19 (1): 108
BACKGROUND: Childhood exposure to air pollution contributes to cardiovascular disease in adulthood. Immune and oxidative stress disturbances might mediate the effects of air pollution on the cardiovascular system, but the underlying mechanisms are poorly understood in adolescents. Therefore, we aimed to identify immune biomarkers linking air pollution exposure and blood pressure levels in adolescents.METHODS: We randomly recruited 100 adolescents (mean age, 16years) from Fresno, California. Using central-site data, spatial-temporal modeling, and distance weighting exposures to the participant's home, we estimated average pollutant levels [particulate matter (PM), polyaromatic hydrocarbons (PAH), ozone (O3), carbon monoxide (CO) and nitrogen oxides (NOx)]. We collected blood samples and vital signs on health visits. Using proteomic platforms, we quantitated markers of inflammation, oxidative stress, coagulation, and endothelial function. Immune cellular characterization was performed via mass cytometry (CyTOF). We investigated associations between pollutant levels, cytokines, immune cell types, and blood pressure (BP) using partial least squares (PLS) and linear regression, while adjusting for important confounders.RESULTS: Using PLS, biomarkers explaining most of the variance in air pollution exposure included markers of oxidative stress (GDF-15 and myeloperoxidase), acute inflammation (C-reactive protein), hemostasis (ADAMTS, D-dimer) and immune cell types such as monocytes. Most of these biomarkers were independently associated with the air pollution levels in fully adjusted regression models. In CyTOF analyses, monocytes were enriched in participants with the highest versus the lowest PM2.5 exposure. In both PLS and linear regression, diastolic BP was independently associated with PM2.5, NO, NO2, CO and PAH456 pollution levels (P≤0.009). Moreover, monocyte levels were independently related to both air pollution and diastolic BP levels (P≤0.010). In in vitro cell assays, plasma of participants with high PM2.5 exposure induced endothelial dysfunction as evaluated by eNOS and ICAM-1 expression and tube formation.CONCLUSIONS: For the first time in adolescents, we found that ambient air pollution levels were associated with oxidative stress, acute inflammation, altered hemostasis, endothelial dysfunction, monocyte enrichment and diastolic blood pressure. Our findings provide new insights on pollution-related immunological and cardiovascular disturbances and advocate preventative measures of air pollution exposure.
View details for DOI 10.1186/s12940-020-00662-2
View details for PubMedID 33066786
Quantifying the Influence of Wedge Pressure, Age, and Heart Rate on the Systolic Thresholds for Detection of Pulmonary Hypertension.
Journal of the American Heart Association
Background The strong linear relation between mean (MPAP) and systolic (SPAP) pulmonary arterial pressure (eg, SPAP=1.62*MPAP) has been mainly reported in precapillary pulmonary hypertension. This study sought to quantify the influence of pulmonary arterial wedge pressure (PAWP), heart rate, and age on the MPAP-SPAP relation. Methods and Results An allometric equation relating invasive MPAP and SPAP was developed in 1135 patients with pulmonary arterial hypertension, advanced lung disease, chronic thromboembolic pulmonary hypertension, or left heart failure. The equation was validated in 60885 patients from the United Network for Organ Sharing (UNOS) database referred for heart and/or lung transplant. The MPAP/SPAP longitudinal stability was assessed in pulmonary arterial hypertension with repeated right heart catheterization. The equation obtained was SPAP=1.39*MPAP*PAWP-0.07*(60/heart rate)0.12*age0.08 (P<0.001). It was validated in the UNOS cohort (R2=0.93, P<0.001), regardless of the type of organ(s) patients were listed for (mean bias [-1.96SD; 1.96SD] was 0.94 [-8.00; 9.88] for heart, 1.34 [-7.81; 10.49] for lung and 0.25 [-16.74; 17.24] mmHg for heart-lung recipients). Thresholds of SPAP for MPAP=25 and 20mmHg were lower in patients with higher PAWP (37.2 and 29.8mmHg) than in those with pulmonary arterial hypertension (40.1 and 32.0mmHg). In 186 patients with pulmonary arterial hypertension, the predicted MPAP/SPAP was stable over time (0.63±0.03 at baseline and follow-up catheterization, P=0.43). Conclusions This study quantifies the impact of PAWP, and to a lesser extent heart rate and age, on the MPAP-SPAP relation, supporting lower SPAP thresholds for pulmonary hypertension diagnosis in patients with higher PAWP for echocardiography-based epidemiological studies.
View details for DOI 10.1161/JAHA.119.016265
View details for PubMedID 32419583
The Environment-sensing Aryl-hydrocarbon Receptor Inhibits the Chondrogenic Fate of Modulated Smooth Muscle Cells in Atherosclerotic Lesions
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000607042600157
Cumulative Lifetime Burden of Cardiovascular Disease From Early Exposure to Air Pollution.
Journal of the American Heart Association
2020; 9 (6): e014944
The disease burden associated with air pollution continues to grow. The World Health Organization (WHO) estimates ≈7 million people worldwide die yearly from exposure to polluted air, half of which-3.3 million-are attributable to cardiovascular disease (CVD), greater than from major modifiable CVD risks including smoking, hypertension, hyperlipidemia, and diabetes mellitus. This serious and growing health threat is attributed to increasing urbanization of the world's populations with consequent exposure to polluted air. Especially vulnerable are the elderly, patients with pre-existing CVD, and children. The cumulative lifetime burden in children is particularly of concern because their rapidly developing cardiopulmonary systems are more susceptible to damage and they spend more time outdoors and therefore inhale more pollutants. World Health Organization estimates that 93% of the world's children aged <15 years-1.8 billion children-breathe air that puts their health and development at risk. Here, we present growing scientific evidence, including from our own group, that chronic exposure to air pollution early in life is directly linked to development of major CVD risks, including obesity, hypertension, and metabolic disorders. In this review, we surveyed the literature for current knowledge of how pollution exposure early in life adversely impacts cardiovascular phenotypes, and lay the foundation for early intervention and other strategies that can help prevent this damage. We also discuss the need for better guidelines and additional research to validate exposure metrics and interventions that will ultimately help healthcare providers reduce the growing burden of CVD from pollution.
View details for DOI 10.1161/JAHA.119.014944
View details for PubMedID 32174249
Spontaneous Coronary Artery Dissection and ST-Segment Elevation Myocardial Infarction in an Anomalous LAD Artery
JACC: Case Reports
View details for DOI 10.1016/j.jaccas.2019.11.061
Molecular mechanisms of coronary disease revealed using quantitative trait loci for TCF21 binding, chromatin accessibility, and chromosomal looping.
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.
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
- Immunologic effects of forest fire exposure show increases in IL-1β and CRP. Allergy 2020
Coronary Disease Associated Gene TCF21 Inhibits Smooth Muscle Cell Differentiation by Blocking the Myocardin-Serum Response Factor Pathway.
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
Utility of High-Sensitivity and Conventional Troponin in Patients Undergoing Transcatheter Aortic Valve Replacement: Incremental Prognostic Value to B-type Natriuretic Peptide.
2019; 9 (1): 14936
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±16.0mmHg and AVA of 0.63±0.19cm2. When using a threshold of 6ng/L, 77% had positive hs-TnI while 27% had positive hs-TnI using recommended thresholds (16ng/L for female and 34ng/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.
View details for DOI 10.1038/s41598-019-51371-x
View details for PubMedID 31624275
Aortic Lumen Area Modifies the Association Between Aortic Calcification and Mortality After Transcatheter Aortic Valve Replacement
ELSEVIER SCIENCE INC. 2019: B701
View details for Web of Science ID 000487306300702
PM2.5 concentration in the ambient air is a risk factor for the development of high-risk coronary plaques.
European heart journal cardiovascular Imaging
AIMS: We aimed to investigate whether long-term exposure to particulate matter with an aerodynamic diameter <2.5mum (PM2.5) in the ambient air is related to the development or growth of coronary plaques.METHODS AND RESULTS: This study involved 364 residents of Seoul, Korea, who underwent serial coronary computed tomographic angiography (CCTA) at an interval of ≥2years. Each participant's average concentration of residential PM2.5 between the two CCTAs was calculated. Primary endpoint was the development of high-risk plaque (HRP), defined as a plaque with low attenuation, spotty calcium, and positive remodelling. Secondary endpoints were the volume increase of total plaque and its component volume. Among those without HRP at baseline (n=341), 20 patients developed HRP at follow-up CCTA, the residential PM2.5 concentration of which was significantly higher than those without HRP at follow-up (25.8±2.0 vs. 25.0±1.7mug/m3 for patients with newly developed HRP vs. patients without HRP at follow-up; P=0.047). An increase in PM2.5 concentration was associated with increased incidence of HRP at follow-up [adjusted hazard ratio (aHR) 1.62, 95% confidence interval (CI) 1.22-2.15, P<0.001]. In a secondary analysis, the PM2.5 concentration was associated with an increased risk of the formation of either fibrofatty or necrotic core component in newly developed plaques (aHR 1.41, 95% CI 1.23-1.61, P<0.001), and with a higher risk of total plaque volume progression in the pre-existing plaques (aHR 1.14, 95% CI 1.05-1.23, P=0.002).CONCLUSION: Exposure to higher concentration of PM2.5 in the ambient air is significantly associated with the development of high-risk coronary plaques.
View details for DOI 10.1093/ehjci/jez209
View details for PubMedID 31410457
Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis.
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.
View details for DOI 10.1038/s41591-019-0512-5
View details for PubMedID 31359001
- TCF21 and AP-1 interact through epigenetic modifications to regulate coronary artery disease gene expression GENOME MEDICINE 2019; 11
- Incremental value of calcifications of the aortomitral continuity after transcatheter aortic valve replacement. Radiology: Cardiothoracic Imaging 2019; 1 (5)
Incremental Value of Aortomitral Continuity Calcification for Risk Assessment after Transcatheter Aortic Valve Replacement.
Radiology. Cardiothoracic imaging
2019; 1 (5): e190067
To investigate the association of aortomitral continuity calcification (AMCC) with all-cause mortality, postprocedural paravalvular leak (PVL), and prolonged hospital stay in patients undergoing transcatheter aortic valve replacement (TAVR).The authors retrospectively evaluated 329 patients who underwent TAVR between March 2013 and March 2016. AMCC, aortic valve calcification (AVC), and coronary artery calcification (CAC) were quantified by using preprocedural CT. Pre-procedural Society of Thoracic Surgeons (STS) score was recorded. Associations between baseline AMCC, AVC, and CAC and 1-year mortality, PVL, and hospital stay longer than 7 days were analyzed.The median follow-up was 415 days (interquartiles, 344-727 days). After 1 year, 46 of the 329 patients (14%) died and 52 (16%) were hospitalized for more than 7 days. Of the 326 patients who underwent postprocedural echocardiography, 147 (45%) had postprocedural PVL. The CAC score (hazard ratio: 1.11 per 500 points) and AMCC mass (hazard ratio: 1.13 per 500 mg) were associated with 1-year mortality. AVC mass (odds ratio: 1.93 per 100 mg) was associated with postprocedural PVL. Only the STS score was associated with prolonged hospital stay (odds ratio: 1.19 per point).AMCC is associated with mortality within 1 year after TAVR and substantially improves individual risk classification when added to a model consisting of STS score and AVC mass only.Supplemental material is available for this article.© RSNA, 2019See also the commentary by Brown and Leipsic in this issue.
View details for DOI 10.1148/ryct.2019190067
View details for PubMedID 33778530
View details for PubMedCentralID PMC7977784
TCF21 and AP-1 interact through epigenetic modifications to regulate coronary artery disease gene expression.
2019; 11 (1): 23
Genome-wide association studies have identified over 160 loci that are associated with coronary artery disease. As with other complex human diseases, risk in coronary disease loci is determined primarily by altered expression of the causal gene, due to variation in binding of transcription factors and chromatin-modifying proteins that directly regulate the transcriptional apparatus. We have previously identified a coronary disease network downstream of the disease-associated transcription factor TCF21, and in work reported here extends these studies to investigate the mechanisms by which it interacts with the AP-1 transcription complex to regulate local epigenetic effects in these downstream coronary disease loci.Genomic studies, including chromatin immunoprecipitation sequencing, RNA sequencing, and protein-protein interaction studies, were performed in human coronary artery smooth muscle cells.We show here that TCF21 and JUN regulate expression of two presumptive causal coronary disease genes, SMAD3 and CDKN2B-AS1, in part by interactions with histone deacetylases and acetyltransferases. Genome-wide TCF21 and JUN binding is jointly localized and particularly enriched in coronary disease loci where they broadly modulate H3K27Ac and chromatin state changes linked to disease-related processes in vascular cells. Heterozygosity at coronary disease causal variation, or genome editing of these variants, is associated with decreased binding of both JUN and TCF21 and loss of expression in cis, supporting a transcriptional mechanism for disease risk.These data show that the known chromatin remodeling and pioneer functions of AP-1 are a pervasive aspect of epigenetic control of transcription, and thus, the risk in coronary disease-associated loci, and that interaction of AP-1 with TCF21 to control epigenetic features, contributes to the genetic risk in loci where they co-localize.
View details for PubMedID 31014396
Single Cell Characterization of Smooth Muscle Cell Phenotypic Modulation in vivo Reveals a Critical Role for the Coronary Disease Gene Tcf21 in Mice and Humans
LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000528619403025
Cytokines profile of reverse cardiac remodeling following transcatheter aortic valve replacement.
International journal of cardiology
2018; 270: 83–88
OBJECTIVE: Previous studies have suggested that cytokines and growth factors may predict ventricular recovery following aortic valve replacement (AVR). The primary objective of this study was to identify cytokines that predict ventricular recovery following transcatheter AVR (TAVR).METHODS: We prospectively enrolled 121 consecutive patients who underwent TAVR. Standard echocardiographic assessment at baseline, 1-month and 1-year after TAVR included left ventricular (LV) mass index (LVMI) and global longitudinal strain (GLS). Blood samples were obtained at the time of the procedure to measure cytokines using a 63-plex Luminex platform. Partial least squares-discriminant analysis was performed to identify cytokines associated with ventricular remodeling and function at baseline as well as 1 year after TAVR.RESULTS: The mean age was 84 ± 9 years, with a majority of male subjects (59%), a mean LVMI of 120.4 ± 45.1 g/m2 and LVGLS of -13.0 ± 3.2%. On average, LV mass decreased by 8.1% and GLS improved by 20.3% at 1 year following TAVR. Among cytokines assayed, elevated hepatocyte growth factor (HGF) emerged as a common factor significantly associated with worse baseline LVMI and GLS as well as reduced ventricular recovery (p < 0.005). Other factors associated with ventricular recovery included a select group of vascular growth factors, inflammatory mediators and tumor necrosis factors, including VEGF-D, ICAM-1, TNFbeta, and IL1beta.CONCLUSION: We identified a network of cytokines, including HGF, that are significantly correlated with baseline LVMI and GLS, and ventricular recovery following TAVR.
View details for PubMedID 30219541
- Cytokines profile of reverse cardiac remodeling following transcatheter aortic valve replacement INTERNATIONAL JOURNAL OF CARDIOLOGY 2018; 270: 83–88
- Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk PLOS GENETICS 2018; 14 (10)
Expanding transcatheter aortic valve replacement into uncharted indications.
The Korean journal of internal medicine
2018; 33 (3): 474–82
Since the first-in-man transcatheter delivery of an aortic valve prosthesis in 2002, the landscape of aortic stenosis therapeutics has shifted dramatically. While initially restricted to non-surgical cases, progressive advances in transcatheter aortic valve replacement and our understanding of its safety and efficacy have expanded its use in intermediate and possibly low surgical risk patients. In this review, we explore the past, present, and future of transcatheter aortic valve replacement.
View details for PubMedID 29551053
Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk.
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
Dynamic changes in aortic impedance after transcatheter aortic valve replacement and its impact on exploratory outcome.
international journal of cardiovascular imaging
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(2)/ml), stroke volume index (=35 ml/m(2)), and GLS (=-15%) cutoffs. The mean GLS was reduced (-13.0 ± 3.2%). The mean Zva was 5.2 ± 1.6 mmHg*m(2)/ml with 55% of values ≥5.0 mmHg*m(2)/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(2)/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.
View details for DOI 10.1007/s10554-017-1155-6
View details for PubMedID 28516313
TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells.
2017; 13 (5)
Both environmental factors and genetic loci have been associated with coronary artery disease (CAD), however gene-gene and gene-environment interactions that might identify molecular mechanisms of risk are not easily studied by human genetic approaches. We have previously identified the transcription factor TCF21 as the causal CAD gene at 6q23.2 and characterized its downstream transcriptional network that is enriched for CAD GWAS genes. Here we investigate the hypothesis that TCF21 interacts with a downstream target gene, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the cellular response to environmental contaminants, including dioxin and polycyclic aromatic hydrocarbons (e.g., tobacco smoke). Perturbation of TCF21 expression in human coronary artery smooth muscle cells (HCASMC) revealed that TCF21 promotes expression of AHR, its heterodimerization partner ARNT, and cooperates with these factors to upregulate a number of inflammatory downstream disease related genes including IL1A, MMP1, and CYP1A1. TCF21 was shown to bind in AHR, ARNT and downstream target gene loci, and co-localization was noted for AHR-ARNT and TCF21 binding sites genome-wide in regions of HCASMC open chromatin. These regions of co-localization were found to be enriched for GWAS signals associated with cardio-metabolic as well as chronic inflammatory disease phenotypes. Finally, we show that similar to TCF21, AHR gene expression is increased in atherosclerotic lesions in mice in vivo using laser capture microdissection, and AHR protein is localized in human carotid atherosclerosis lesions where it is associated with protein kinases with a critical role in innate immune response. These data suggest that TCF21 can cooperate with AHR to activate an inflammatory gene expression program that is exacerbated by environmental stimuli, and may contribute to the overall risk for CAD.
View details for DOI 10.1371/journal.pgen.1006750
View details for PubMedID 28481916
THE INFLAMMASOME PATHWAY IS ASSOCIATED WITH ADVERSE VENTRICULAR REMODELING FOLLOWING TRANSCATHETER AORTIC VALVE REPLACEMENT
ELSEVIER SCIENCE INC. 2017: 1040
View details for Web of Science ID 000397342301562
GDF-15 (Growth Differentiation Factor 15) Is Associated With Lack of Ventricular Recovery and Mortality After Transcatheter Aortic Valve Replacement.
Circulation. Cardiovascular interventions
2017; 10 (12)
Recent data suggest that circulating biomarkers may predict outcome in patients undergoing transcatheter aortic valve replacement (TAVR). We examined the association between inflammatory, myocardial, and renal biomarkers and their role in ventricular recovery and outcome after TAVR.A total of 112 subjects undergoing TAVR were included in the prospective registry. Plasma levels of B-type natriuretic peptide, hs-TnI (high-sensitivity troponin I), CRP (C-reactive protein), GDF-15 (growth differentiation factor 15), GAL-3 (galectin-3), and Cys-C (cystatin-C) were assessed before TAVR and in 100 sex-matched healthy controls. Among echocardiographic parameters, we measured global longitudinal strain, indexed left ventricular mass, and indexed left atrial volume. The TAVR group included 59% male, with an average age of 84 years, and 1-year mortality of 18%. Among biomarkers, we found GDF-15 and CRP to be strongly associated with all-cause mortality (P<0.001). Inclusion of GDF-15 and CRP to the Society of Thoracic Surgeons score significantly improved C index (0.65-0.79; P<0.05) and provided a category-free net reclassification improvement of 106% at 2 years (P=0.01). Among survivors, functional recovery in global longitudinal strain (>15% improvement) and indexed left ventricular mass (>20% decrease) at 1 year occurred in 48% and 22%, respectively. On multivariate logistic regression, lower baseline GDF-15 was associated with improved global longitudinal strain at 1 year (hazard ratio=0.29; P<0.001). Furthermore, improvement in global longitudinal strain at 1 month correlated with lower overall mortality (hazard ratio=0.45; P=0.03).Elevated GDF-15 correlates with lack of reverse remodeling and increased mortality after TAVR and improves risk prediction of mortality when added to the Society of Thoracic Surgeons score.
View details for PubMedID 29222133
A Computational Framework for Age-at-Death Estimation from the Skeleton: Surface and Outline Analysis of 3D Laser Scans of the Adult Pubic Symphysis
Journal of Forensic Sciences
In forensic anthropology, age-at-death estimation typically requires the macroscopic assessment of the skeletal indicator and its association with a phase or score. High subjectivity and error are the recognized disadvantages of this approach, creating a need for alternative tools that enable the objective and mathematically robust assessment of true chronological age. We describe, here, three fully computational, quantitative shape analysis methods and a combinatory approach that make use of three-dimensional laser scans of the pubic symphysis. We report a novel age-related shape measure, focusing on the changes observed in the ventral margin curvature, and refine two former methods, whose measures capture the flatness of the symphyseal surface. We show how we can decrease age-estimation error and improve prior results by combining these outline and surface measures in two multivariate regression models. The presented models produce objective age-estimates that are comparable to current practices with root-mean-square-errors between 13.7 and 16.5 years.
View details for DOI 10.1111/1556-4029.13439
Moving Beyond Linear Formulas for Left Ventricular Mass in Aortic Valve Replacement
View details for DOI 10.1080/24748706.2017.1377364
- Moving beyond linear formulas for left ventricular mass in aortic valve replacement Structural Heart: The Journal of the Heart Team 2017; 1 (2)
Incremental Value of Deformation Imaging and Hemodynamics Following Heart Transplantation: Insights From Graft Function Profiling.
JACC. Heart failure
2017; 5 (12): 930–39
This study investigated to define graft dysfunction and to determine its incremental association with long-term outcome after heart transplantation (HT).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.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.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/m2, 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.RAP and LVGLS at the first annual evaluation provide complementary prognostic information in predicting 5-year outcome after HT.
View details for PubMedID 29191301
Genetics and Genomics of Coronary Artery Disease.
Current cardiology reports
2016; 18 (10): 102-?
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.
View details for DOI 10.1007/s11886-016-0777-y
View details for PubMedID 27586139
Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci.
2016; 7: 12092-?
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.
View details for DOI 10.1038/ncomms12092
View details for PubMedID 27386823
Effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory metastatic basal cell carcinoma
Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.Of the 5 patients (mean [SD] age, 52  years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients.Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.
View details for DOI 10.1001/jamadermatol.2015.5473
Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells that Contribute to the Fibrous Cap.
2015; 5: 36-37
TCF21 is a basic helix-loop-helix transcription factor that has recently been implicated as contributing to susceptibility to coronary heart disease based on genome wide association studies. In order to identify transcriptionally regulated target genes in a major disease relevant cell type, we performed siRNA knockdown of TCF21 in in vitro cultured human coronary artery smooth muscle cells and compared the transcriptome of siTCF21 versus siCONTROL treated cells. The raw (FASTQ) as well as processed (BED) data from 3 technical replicates per treatment has been deposited with Gene Expression Omnibus (GSE44461).
View details for PubMedID 26090325
Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci
2015; 11 (5)
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.
View details for DOI 10.1371/journal.pgen.1005202
View details for Web of Science ID 000355305200022
View details for PubMedID 26020271
Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells That Contribute to the Fibrous Cap
2015; 11 (5)
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.
View details for DOI 10.1371/journal.pgen.1005155
View details for Web of Science ID 000355305200011
View details for PubMedID 26020946
- Continuous flow left ventricular assist device placement complicated by aortic valve thrombus and myocardial infarction INTERNATIONAL JOURNAL OF CARDIOLOGY 2014; 176 (3): E102-E103
- Presence of plaques predicts worse outcomes in multi-detector computed tomography in patients with stable chest pain syndrome INTERNATIONAL JOURNAL OF CARDIOLOGY 2014; 173 (3): 570-572
Heart Failure is Associated With Impaired Anti-Inflammatory and Antioxidant Properties of High-Density Lipoproteins
AMERICAN JOURNAL OF CARDIOLOGY
2013; 112 (11): 1770-1777
Oxidative stress and inflammation are hallmarks of the heart failure (HF) disease state. In the present study, we investigated the inflammatory/anti-inflammatory characteristics of high-density lipoproteins (HDL) in patients with HF. Ninety-six consecutive patients with systolic HF were followed in an advanced HF center, and 21 healthy subjects were recruited. Plasma was tested for HDL inflammatory index (HII) using a monocyte chemotactic activity assay, with HII >1.0 indicating proinflammatory HDL. We found significantly increased inflammatory properties of HDL in patients with HF (median HII 1.56 vs 0.59 in controls; p <0.0001). Serum amyloid A level was markedly elevated and the activity of paraoxonase-1, an HDL antioxidant enzyme, was significantly reduced in patients versus controls. HDL and albumin from patients with HF contained markedly elevated levels of oxidized products of arachidonic and linoleic acids. HDL function improved when plasma was treated in vitro with 4F, an apolipoprotein A-I mimetic peptide (40% reduction in HII, p <0.0001). There was no correlation found between HII level and ejection fraction or New York Heart Association functional class. In conclusion, HDL function is significantly impaired and oxidation products of arachidonic and linoleic acids are markedly elevated in patients with HF compared with non-HF controls.
View details for DOI 10.1016/j.amjcard.2013.07.045
View details for Web of Science ID 000327685900012
View details for PubMedID 24050409
- Anti-Inflammatory Strategies for Plaque Stabilization after Acute Coronary Syndromes (vol 15, 327, 2013) CURRENT ATHEROSCLEROSIS REPORTS 2013; 15 (12)
Anti-Inflammatory Strategies for Plaque Stabilization after Acute Coronary Syndromes
CURRENT ATHEROSCLEROSIS REPORTS
2013; 15 (6)
Despite dramatic advances in standard of care, the risk of recurrent myocardial infarction early after an acute coronary syndrome (ACS) remains high. This period of elevated risk after a cardiovascular event is associated with an acute inflammatory response. While post-ACS inflammation correlates with the risk for recurrent events and is likely to play a causal role in this period, the precise pathophysiologic mechanisms have been unclear. Recent studies have proposed that the cardiac event itself activates the sympathetic nervous system to directly mobilize hematopoietic stem cells to differentiate into inflammatory monocytes, acutely infiltrate plaque, and lead to recurrent plaque rupture. Here, we summarize the existing and emerging evidence implicating post-ACS activation of systemic inflammation in the progression of atherosclerosis, and identify possible targets for therapeutic intervention. We highlight experimental therapies and ongoing clinical studies that will validate these targets.
View details for DOI 10.1007/s11883-013-0327-7
View details for Web of Science ID 000320656500002
View details for PubMedID 23636864
Effect of 9p21.3 coronary artery disease locus neighboring genes on atherosclerosis in mice.
2012; 126 (15): 1896-1906
The human 9p21.3 chromosome locus has been shown to be an independent risk factor for atherosclerosis in multiple large-scale genome-wide association studies, but the underlying mechanism remains unknown. We set out to investigate the potential role of the 9p21.3 locus neighboring genes, including Mtap, the 2 isoforms of Cdkn2a, p16Ink4a and p19Arf, and Cdkn2b, in atherosclerosis using knockout mice models.Gene-targeted mice for neighboring genes, including Mtap, Cdkn2a, p19Arf, and Cdkn2b, were each bred to mice carrying the human APO*E3 Leiden transgene that sensitizes the mice for atherosclerotic lesions through elevated plasma cholesterol. We found that the mice heterozygous for Mtap developed larger lesions compared with wild-type mice (49623±21650 versus 18899±9604 μm(2) per section [mean±SD]; P=0.01), with morphology similar to that of wild-type mice. The Mtap heterozygous mice demonstrated changes in metabolic and methylation profiles and CD4(+) cell counts. The Cdkn2a knockout mice had smaller lesions compared with wild-type and heterozygous mice, and there were no significant differences in lesion size in p19Arf and Cdkn2b mutants compared with wild type. We observed extensive, tissue-specific compensatory regulation of the Cdkn2a and Cdkn2b genes among the various knockout mice, making the effects on atherosclerosis difficult to interpret.Mtap plays a protective role against atherosclerosis, whereas Cdkn2a appears to be modestly proatherogenic. However, no relation was found between the 9p21 genotype and the transcription of 9p21 neighboring genes in primary human aortic vascular cells in vitro. There is extensive compensatory regulation in the highly conserved 9p21 orthologous region in mice.
View details for DOI 10.1161/CIRCULATIONAHA.111.064881
View details for PubMedID 22952318
View details for PubMedCentralID PMC3608429
Paraoxonase-2 Modulates Stress Response of Endothelial Cells to Oxidized Phospholipids and a Bacterial Quorum-Sensing Molecule
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2011; 31 (11): 2624-U688
Chronic infection has long been postulated as a stimulus for atherogenesis. Pseudomonas aeruginosa infection has been associated with increased atherosclerosis in rats, and these bacteria produce a quorum-sensing molecule 3-oxo-dodecynoyl-homoserine lactone (3OC12-HSL) that is critical for colonization and virulence. Paraoxonase 2 (PON2) hydrolyzes 3OC12-HSL and also protects against the effects of oxidized phospholipids thought to contribute to atherosclerosis. We now report the response of human aortic endothelial cells (HAECs) to 3OC12-HSL and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) in relation to PON2 expression.Using expression profiling and network modeling, we identified the unfolded protein response (UPR), cell cycle genes, and the mitogen-activated protein kinase signaling pathway to be heavily involved in the HAEC response to 3OC12-HSL. The network also showed striking similarities to a network created based on HAEC response to Ox-PAPC, a major component of minimally modified low-density lipoprotein. HAECs in which PON2 was silenced by small interfering RNA showed increased proinflammatory response and UPR when treated with 3OC12-HSL or Ox-PAPC.3OC12-HSL and Ox-PAPC influence similar inflammatory and UPR pathways. Quorum sensing molecules, such as 3OC12-HSL, contribute to the proatherogenic effects of chronic infection. The antiatherogenic effects of PON2 include destruction of quorum sensing molecules.
View details for DOI 10.1161/ATVBAHA.111.232827
View details for Web of Science ID 000296605400037
View details for PubMedID 21836061
View details for PubMedCentralID PMC3244174
The Effect of HDL Mimetic Peptide 4F on PON1
3rd International Conference on Paraoxonases
SPRINGER-VERLAG BERLIN. 2010: 167–172
Several lines of evidence indicate that serum paraoxonase 1 (PON1) acts as an important guardian against cellular damage from oxidized lipids in plasma membrane, in low-density lipoprotein (LDL), against bacterial endotoxin and against toxic agents such as pesticide residues including organophosphates. In circulation, the high-density lipoprotein (HDL)-associated PON1 has the ability to prevent the formation of proinflammatory oxidized phospholipids. These oxidized phospholipids negatively regulate the activities of the HDL-associated PON1 and several other anti-inflammatory factors in HDL. During the acute phase response in rabbits, mice, and humans, there appears to be an increase in the formation of these oxidized lipids that results in the inhibition of the HDL-associated PON1 and an association of acute phase proteins with HDL that renders HDL proinflammatory. Low serum HDL is a risk factor for atherosclerosis and attempts are directed toward therapies to improve the quality and the relative concentrations of LDL and HDL. Apolipoprotein A-I (apoA-I) has been shown to reduce atherosclerotic lesions in laboratory animals. ApoA-I, however, is a large protein and needs to be administered parenterally, and it is costly. We have developed apoA-I mimetic peptides that are much smaller than apoA-I, and much more effective in removing the oxidized phospholipids and other oxidized lipids. These mimetic peptides improve LDL and HDL composition and function and reduce lesion formation in animal models of atherogenesis. Following is a brief description of some of the HDL mimetic peptides that can improve HDL and the effect of the peptide on PON1 activity.
View details for DOI 10.1007/978-1-60761-350-3_15
View details for Web of Science ID 000276140000015
View details for PubMedID 20221879
- Dyslipidemia and cardiovascular diseases CURRENT OPINION IN LIPIDOLOGY 2009; 20 (2): 157-158
The effect of transvenous pacemaker and implantable cardioverter defibrillator lead placement on tricuspid valve function: An observational study
JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY
2008; 21 (3): 284-287
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).
View details for DOI 10.1016/j.echo.2007.05.022
View details for Web of Science ID 000254081900014
View details for PubMedID 17604958
Cyclooxygenase-2 inhibits novel ginseng metabolite-mediated apoptosis
2005; 65 (5): 1952-1960
Recently, a novel intestinal bacterial metabolite of ginseng protopanaxadiol saponins, i.e., 20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol (IH-901), has been reported to induce apoptosis in a variety of cancer cells. Here we show a differential effect of IH-901 on several cell types. Exposure to IH-901 for 48 hours at a supposedly subapoptotic concentration of 40 mumol/L led to both apoptotic cell death and G1 arrest in Hep3B cells, but only resulted in G1 arrest in MDA-MB-231, Hs578T, and MKN28 cells. Additionally, the treatment of MDA-MB-231, but not of Hep3B, with IH-901 up-regulated cyclooxygenase-2 (COX-2) mRNA (2 hours) and protein (6 hours), and enhanced the production of prostaglandin E2. In MDA-MB-231 cells, IH-901 induced the sustained activation of extracellular signal-regulated kinase (ERK), whereas inhibition of mitogen-activated protein/ERK kinase blocked IH-901-mediated COX-2 induction and resulted in apoptosis, suggesting the involvement of an ERK-COX-2 pathway. Combined treatment with IH-901 and nonsteroidal anti-inflammatory drugs inhibited COX-2 enzyme and induced apoptosis in MDA-MB-231 and Hs578T cells. Adenovirus-mediated COX-2 small interfering RNAs also effectively inhibited COX-2 protein expression and enhanced IH-901-mediated apoptosis without inhibiting ERK 1/2 phosphorylation, thus providing direct evidence that COX-2 is an antiapoptotic molecule. Moreover, IH-901-mediated G1 arrest resulted from an increase in p27Kip1 mRNA and protein expression followed by a decrease in CDK2 kinase activity that was concurrent with the hypophosphorylation of Rb and p130. In conclusion, IH-901 induced both G1 arrest and apoptosis, and this apoptosis could be inhibited by COX-2 induction.
View details for DOI 10.1158/0008-5472.CAN-04-1740
View details for Web of Science ID 000227294600043
View details for PubMedID 15753395