- Vascular Medicine
- Cardiovascular Disease
Fellowship:Stanford University School of Medicine (2009) CA
Board Certification: Cardiovascular Disease, American Board of Internal Medicine (2009)
Residency:UCSF-Graduate Medical Education (2005) CA
Medical Education:Univ Of Chicago - Registrar (2003) IL
Board Certification: Internal Medicine, American Board of Internal Medicine (2006)
PRESERVE-Zenith® Iliac Branch System Clinical Study
The PRESERVE-Zenith® Iliac Branch System Clinical Study is a clinical trial to study the safety and effectiveness of the Zenith® Branch Endovascular Graft-Iliac Bifurcation in combination with the Zenith® Connection Endovascular Stent/ConnectSX™ covered stent in the treatment of aorto-iliac and iliac aneurysms.
Patients With Intermittent Claudication Injected With ALDH Bright Cells
The purpose of this study is to find out if aldehyde dehydrogenase bright (ALDHbr) cells taken from a patient's bone marrow can be placed safely, via intramuscular injections, into their affected calf and lower thigh muscles and improve blood flow and/or peak walking time in patients experiencing pain associated with blocked blood vessels in the leg.
Effect of Proton Pump Inhibitors on Endothelial Function
In this randomized controlled crossover study, the investigators propose to test the hypothesis that proton pump inhibitors (PPIs) increase plasma levels of asymmetric dimethylarginine (ADMA), which is a marker of endothelial dysfunction. The authors propose to evaluate ADMA concentrations and vascular function analysis in healthy volunteers and adults with a history of cardiovascular disease given PPI vs placebo for four weeks each.
The Genetic Basis of Peripheral Arterial Disease Current Knowledge, Challenges, and Future Directions
2015; 116 (9): 1551-1560
Several risk factors for atherosclerotic peripheral arterial disease (PAD), such as dyslipidemia, diabetes mellitus, and hypertension, are heritable. However, predisposition to PAD may be influenced by genetic variants acting independently of these risk factors. Identification of such genetic variants will provide insights into underlying pathophysiologic mechanisms and facilitate the development of novel diagnostic and therapeutic approaches. In contrast to coronary heart disease, relatively few genetic variants that influence susceptibility to PAD have been discovered. This may be, in part, because of greater clinical and genetic heterogeneity in PAD. In this review, we (1) provide an update on the current state of knowledge about the genetic basis of PAD, including results of family studies and candidate gene, linkage as well as genome-wide association studies; (2) highlight the challenges in investigating the genetic basis of PAD and possible strategies to overcome these challenges; and (3) discuss the potential of genome sequencing, RNA sequencing, differential gene expression, epigenetic profiling, and systems biology in increasing our understanding of the molecular genetics of PAD.
View details for DOI 10.1161/CIRCRESAHA.116.303518
View details for Web of Science ID 000353383600005
View details for PubMedID 25908728
- MicroRNA Regulation of Vascular Smooth Muscle Function and Phenotype Early Career Committee Contribution ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 2015; 35 (1): 2-6
Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population.
2015; 10 (6)
Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches.Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09-1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.
View details for DOI 10.1371/journal.pone.0124653
View details for PubMedID 26061035
Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1
JOURNAL OF CLINICAL INVESTIGATION
2014; 124 (12): 5159-5174
Angioplasty and stenting is the primary treatment for flow-limiting atherosclerosis; however, this strategy is limited by pathological vascular remodeling. Using a systems approach, we identified a role for the network hub gene glutathione peroxidase-1 (GPX1) in pathological remodeling following human blood vessel stenting. Constitutive deletion of Gpx1 in atherosclerotic mice recapitulated this phenotype of increased vascular smooth muscle cell (VSMC) proliferation and plaque formation. In an independent patient cohort, gene variant pair analysis identified an interaction of GPX1 with the orphan protooncogene receptor tyrosine kinase ROS1. A meta-analysis of the only genome-wide association studies of human neointima-induced in-stent stenosis confirmed the association of the ROS1 variant with pathological remodeling. Decreased GPX1 expression in atherosclerotic mice led to reductive stress via a time-dependent increase in glutathione, corresponding to phosphorylation of the ROS1 kinase activation site Y2274. Loss of GPX1 function was associated with both oxidative and reductive stress, the latter driving ROS1 activity via s-glutathiolation of critical residues of the ROS1 tyrosine phosphatase SHP-2. ROS1 inhibition with crizotinib and deglutathiolation of SHP-2 abolished GPX1-mediated increases in VSMC proliferation while leaving endothelialization intact. Our results indicate that GPX1-dependent alterations in oxido-reductive stress promote ROS1 activation and mediate vascular remodeling.
View details for DOI 10.1172/JCI77484
View details for Web of Science ID 000345677200011
Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis
JOURNAL OF CLINICAL INVESTIGATION
2014; 124 (3): 1083-1097
Genetic variation at the chromosome 9p21 risk locus promotes cardiovascular disease; however, it is unclear how or which proteins encoded at this locus contribute to disease. We have previously demonstrated that loss of one candidate gene at this locus, cyclin-dependent kinase inhibitor 2B (Cdkn2b), in mice promotes vascular SMC apoptosis and aneurysm progression. Here, we investigated the role of Cdnk2b in atherogenesis and found that in a mouse model of atherosclerosis, deletion of Cdnk2b promoted advanced development of atherosclerotic plaques composed of large necrotic cores. Furthermore, human carriers of the 9p21 risk allele had reduced expression of CDKN2B in atherosclerotic plaques, which was associated with impaired expression of calreticulin, a ligand required for activation of engulfment receptors on phagocytic cells. As a result of decreased calreticulin, CDKN2B-deficient apoptotic bodies were resistant to efferocytosis and not efficiently cleared by neighboring macrophages. These uncleared SMCs elicited a series of proatherogenic juxtacrine responses associated with increased foam cell formation and inflammatory cytokine elaboration. The addition of exogenous calreticulin reversed defects associated with loss of Cdkn2b and normalized engulfment of Cdkn2b-deficient cells. Together, these data suggest that loss of CDKN2B promotes atherosclerosis by increasing the size and complexity of the lipid-laden necrotic core through impaired efferocytosis.
View details for DOI 10.1172/JCI70391
View details for Web of Science ID 000332347700028
Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2014; 111 (7): 2698-2703
Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von Hippel-Lindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1-activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.
View details for DOI 10.1073/pnas.1320243111
View details for Web of Science ID 000331396500062
View details for PubMedID 24497508
Alternative Ankle-Brachial Index Method Identifies Additional At-Risk Individuals
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2013; 62 (6): 553-559
OBJECTIVES: To determine whether utilization of an alternative ankle-brachial index (ABI) calculation method improves mortality risk prediction compared to traditional methods. BACKGROUND: The ABI is used to diagnose peripheral arterial disease (PAD), and to identify those at risk for cardiovascular events. Traditionally, the ABI is calculated using the higher of the dorsalis pedis and posterior tibial ankle arteries. Studies directly comparing calculation methods are limited. METHODS: The ABI was calculated at baseline in 1,413 study participants undergoing non-emergent coronary angiography subsequently followed for all-cause and cardiovascular mortality. There were 224 individuals assigned to the traditional-PAD group (ABI < 0.90) using the traditional ABI method. Of those remaining, an alternative ABI method utilizing the lower of the two ankle pressures assigned 282 patients to the alternative-PAD group. The 862 individuals not assigned to PAD by either method were the no-PAD group. RESULTS: There were 163 mortalities during a median follow-up of 5.0 years. Adjusted Cox regression models showed that the alternative-PAD group had an increased risk for all-cause (HR=1.49; 95% CI, 1.01-2.19) and cardiovascular mortality (HR=3.21; 95% CI, 1.53-6.37) versus the no-PAD group. Additionally, in the no-PAD group, there was an 11% (HR=1.11; 95% CI, 1.05-1.17) increased risk of all-cause mortality per 1mm Hg increased difference between the left and right brachial systolic pressures. CONCLUSION: The implementation of an alternative ABI method and use of the brachial difference identifies individuals at an increased risk for mortality who are currently missed using traditional ABI methods. Current ABI protocols may need to be evaluated.
View details for DOI 10.1016/j.jacc.2013.04.061
View details for Web of Science ID 000322524300011
View details for PubMedID 23707317
- Practice-Based Evidence: Profiling the Safety of Cilostazol by Text-Mining of Clinical Notes PLOS ONE 2013; 8 (5)
Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation.
Arteriosclerosis, thrombosis, and vascular biology
2013; 33 (1): e1-e10
Genomewide association studies have implicated allelic variation at 9p21.3 in multiple forms of vascular disease, including atherosclerotic coronary heart disease and abdominal aortic aneurysm. As for other genes at 9p21.3, human expression quantitative trait locus studies have associated expression of the tumor suppressor gene CDKN2B with the risk haplotype, but its potential role in vascular pathobiology remains unclear.Here we used vascular injury models and found that Cdkn2b knockout mice displayed the expected increase in proliferation after injury, but developed reduced neointimal lesions and larger aortic aneurysms. In situ and in vitro studies suggested that these effects were attributable to increased smooth muscle cell apoptosis. Adoptive bone marrow transplant studies confirmed that the observed effects of Cdkn2b were mediated through intrinsic vascular cells and were not dependent on bone marrow-derived inflammatory cells. Mechanistic studies suggested that the observed increase in apoptosis was attributable to a reduction in MDM2 and an increase in p53 signaling, possibly due in part to compensation by other genes at the 9p21.3 locus. Dual inhibition of both Cdkn2b and p53 led to a reversal of the vascular phenotype in each model.These results suggest that reduced CDKN2B expression and increased smooth muscle cell apoptosis may be one mechanism underlying the 9p21.3 association with aneurysmal disease.
View details for DOI 10.1161/ATVBAHA.112.300399
View details for PubMedID 23162013
- Genetics of Peripheral Artery Disease CIRCULATION 2012; 125 (25): 3220-3228
MicroRNA-21 Blocks Abdominal Aortic Aneurysm Development and Nicotine-Augmented Expansion
SCIENCE TRANSLATIONAL MEDICINE
2012; 4 (122)
Identification and treatment of abdominal aortic aneurysm (AAA) remains among the most prominent challenges in vascular medicine. MicroRNAs are crucial regulators of cardiovascular pathology and represent possible targets for the inhibition of AAA expansion. We identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models. In both models (AAA induced by porcine pancreatic elastase or infusion of angiotensin II), miR-21 expression increased as AAA developed. Lentiviral overexpression of miR-21 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. miR-21 overexpression substantially decreased expression of the phosphatase and tensin homolog (PTEN) protein, leading to increased phosphorylation and activation of AKT, a component of a pro-proliferative and antiapoptotic pathway. Systemic injection of a locked nucleic acid-modified antagomir targeting miR-21 diminished the pro-proliferative impact of down-regulated PTEN, leading to a marked increase in the size of AAA. Similar results were seen in mice with AAA augmented by nicotine and in human aortic tissue samples from patients undergoing surgical repair of AAA (with more pronounced effects observed in smokers). Modulation of miR-21 expression shows potential as a new therapeutic option to limit AAA expansion and vascular disease progression.
View details for DOI 10.1126/scitranslmed.3003441
View details for Web of Science ID 000300952100004
View details for PubMedID 22357537
Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development
JOURNAL OF CLINICAL INVESTIGATION
2012; 122 (2): 497-506
MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.
View details for DOI 10.1172/JCI61598
View details for Web of Science ID 000299765800016
View details for PubMedID 22269326
MicroRNA-26a Is a Novel Regulator of Vascular Smooth Muscle Cell Function
JOURNAL OF CELLULAR PHYSIOLOGY
2011; 226 (4): 1035-1043
Aberrant smooth muscle cell (SMC) plasticity has been implicated in a variety of vascular disorders including atherosclerosis, restenosis, and abdominal aortic aneurysm (AAA) formation. While the pathways governing this process remain unclear, epigenetic regulation by specific microRNAs (miRNAs) has been demonstrated in SMCs. We hypothesized that additional miRNAs might play an important role in determining vascular SMC phenotype. Microarray analysis of miRNAs was performed on human aortic SMCs undergoing phenotypic switching in response to serum withdrawal, and identified 31 significantly regulated entities. We chose the highly conserved candidate miRNA-26a for additional studies. Inhibition of miRNA-26a accelerated SMC differentiation, and also promoted apoptosis, while inhibiting proliferation and migration. Overexpression of miRNA-26a blunted differentiation. As a potential mechanism, we investigated whether miRNA-26a influences TGF-?-pathway signaling. Dual-luciferase reporter assays demonstrated enhanced SMAD signaling with miRNA-26a inhibition, and the opposite effect with miRNA-26a overexpression in transfected human cells. Furthermore, inhibition of miRNA-26a increased gene expression of SMAD-1 and SMAD-4, while overexpression inhibited SMAD-1. MicroRNA-26a was also found to be downregulated in two mouse models of AAA formation (2.5- to 3.8-fold decrease, P?0.02) in which enhanced switching from contractile to synthetic phenotype occurs. In summary, miRNA-26a promotes vascular SMC proliferation while inhibiting cellular differentiation and apoptosis, and alters TGF-? pathway signaling. MicroRNA-26a represents an important new regulator of SMC biology and a potential therapeutic target in AAA disease.
View details for DOI 10.1002/jcp.22422
View details for Web of Science ID 000287258800019
View details for PubMedID 20857419
- MicroRNA and Mechanisms of Impaired Angiogenesis in Diabetes Mellitus CIRCULATION 2011; 123 (3): 236-238
- Stem Cell Therapy for Vascular Regeneration Adult, Embryonic, and Induced Pluripotent Stem Cells CIRCULATION 2010; 122 (5): 517-526
Upregulation of the apelin-APJ pathway promotes neointima formation in the carotid ligation model in mouse
2010; 87 (1): 156-165
To investigate apelin-APJ (angiotensin receptor-like 1) signalling in vascular remodelling, we have examined the pathophysiological response to carotid ligation in apelin knockout mice.Apelin null animals compared with wild-type mice had significantly decreased neointimal lesion area (1.17 +/- 0.17 vs. 3.33 +/- 1.04 x 10(4) microm(2), P < 0.05) and intima/media ratio (0.81 +/- 0.23 vs. 1.49 +/- 0.44, P < 0.05), averaged over four sites 0.5-2 mm from the ligation. Exogenous apelin infusion rescued the apelin-KO phenotype, promoting neointima formation in the null animals. Apelin null animals showed decreased smooth muscle positive area in the neointima (82.3 +/- 2.4 vs. 63.9 +/- 8.4, P < 0.05), and a smaller percentage BrdU positive cells in the neointima and media (11.06 +/- 1.00 vs. 6.53 +/- 0.86, P < 0.05). Apelin mRNA expression increased initially (5.2-fold, P < 0.01) followed by increased apelin receptor expression (10.1-fold, P < 0.05) in the ligated artery. Cytochemistry studies localized apelin expression to luminal endothelial cells and apelin receptor upregulation to smooth muscle cells (SMC) in the media and neointima. In vitro experiments with cultured rat aortic SMC revealed that apelin stimulation increased migration. In contrast to the increased expression of apelin and apelin receptor in carotid remodelling, expression was not upregulated in the apoE high fat model, and correlated with the known disease-inhibitory effect in this model.These data suggest that increased apelin receptor expression by SMC provides a paracrine pathway in injured vessels that allows endothelial-derived apelin to stimulate their division and migration into the neointima.
View details for DOI 10.1093/cvr/cvq052
View details for Web of Science ID 000278690000021
View details for PubMedID 20176814
Apelin prevents aortic aneurysm formation by inhibiting macrophage inflammation
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
2009; 296 (5): H1329-H1335
Apelin is a potent inodilator with recently described antiatherogenic properties. We hypothesized that apelin might also attenuate abdominal aortic aneurysm (AAA) formation by limiting disease-related vascular wall inflammation. C57BL/6 mice implanted with osmotic pumps filled with apelin or saline were treated with pancreatic elastase to create infrarenal AAAs. Mice were euthanized for aortic PCR analysis or followed ultrasonographically and then euthanized for histological analysis. The cellular expression of inflammatory cytokines and chemokines in response to apelin was also assessed in cultured macrophages, smooth muscle cells, and fibroblasts. Apelin treatment resulted in diminished AAA formation, with a 47% reduction in maximal cross-sectional area (0.74 vs. 1.39 mm(2), P < 0.03) and a 57% reduction in macrophage infiltrate (113 vs. 261.3 cells/high-power field, P < 0.0001) relative to the saline-treated group. Apelin infusion was also associated with significantly reduced aortic macrophage colony-stimulating factor expression and decreased monocyte chemattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha mean mRNA levels. Apelin stimulation of cultured macrophages significantly reduced MCP-1 and TNF-alpha mRNA levels relative to baseline (2.03- and 1.89-fold reduction, P < 0.03, respectively) but did not affect intimal adhesion molecule expression or medial or adventitial cell cytokine production. Apelin significantly reduces aneurysm formation in the elastase model of human AAA disease. The mechanism appears to be decreased macrophage burden, perhaps related to an apelin-mediated decrease in proinflammatory cytokine and chemokine activation.
View details for DOI 10.1152/ajpheart.01341.2008
View details for Web of Science ID 000265659100020
View details for PubMedID 19304942
- Clinical problem-solving. Fool's Gold. New England journal of medicine 2008; 359 (19): 2035-2041
Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis
JOURNAL OF CLINICAL INVESTIGATION
2008; 118 (10): 3343-3354
Apelin and its cognate G protein-coupled receptor APJ constitute a signaling pathway with a positive inotropic effect on cardiac function and a vasodepressor function in the systemic circulation. The apelin-APJ pathway appears to have opposing physiological roles to the renin-angiotensin system. Here we investigated whether the apelin-APJ pathway can directly antagonize vascular disease-related Ang II actions. In ApoE-KO mice, exogenous Ang II induced atherosclerosis and abdominal aortic aneurysm formation; we found that coinfusion of apelin abrogated these effects. Similarly, apelin treatment rescued Ang II-mediated increases in neointimal formation and vascular remodeling in a vein graft model. NO has previously been implicated in the vasodepressor function of apelin; we found that apelin treatment increased NO bioavailability in ApoE-KO mice. Furthermore, infusion of an NO synthase inhibitor blocked the apelin-mediated decrease in atherosclerosis and aneurysm formation. In rat primary aortic smooth muscle cells, apelin inhibited Ang II-mediated transcriptional regulation of multiple targets as measured by reporter assays. In addition, we demonstrated by coimmunoprecipitation and fluorescence resonance energy transfer analysis that the Ang II and apelin receptors interacted physically. Taken together, these findings indicate that apelin signaling can block Ang II actions in vascular disease by increasing NO production and inhibiting Ang II cellular signaling.
View details for DOI 10.1172/JCI34871
View details for Web of Science ID 000259828600016
View details for PubMedID 18769630
Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival
2007; 116 (6): 613-618
Aggressive lipid management has recently become the standard of care for patients with coronary heart disease. The safety and effectiveness of statin usage for patients with extremely low low-density lipoprotein (LDL) levels are less clear, however. The aim of this study was to investigate the safety and clinical outcomes of statin treatment in patients with LDL cholesterol levels below 60 mg/dL.A total of 6107 consecutive patients with LDL levels less than 60 mg/dL were identified from a tertiary care medical center or affiliated community clinic. Statin therapy was defined as a prescription during the 150 days after the low LDL value was obtained. The propensity to be treated with a statin was used to adjust the association of statin therapy and survival. A total of 4295 patients (70%) had at least 1 prescription for any medication during the 150-day observation period after the low LDL value. Their mean age was 65 years, 43% had prior ischemic heart disease, and 47% had diabetes mellitus. Statins were prescribed in 2564 patients (60%) after the low LDL value was observed. During a mean follow-up of 2.0+/-1.4 years after the observation period, there were 510 deaths. After controlling for the propensity to receive a statin, statin therapy was associated with improved survival (hazard ratio [HR], 0.65; 95% CI, 0.53 to 0.80). This lower mortality was also observed for subgroups of patients already taking statins at baseline (HR, 0.58; 95% CI, 0.38 to 0.88), those with extremely low LDL levels (<40 mg/dL, n=623; HR, 0.51; 95% CI, 0.33 to 0.79), and those without a history of ischemic heart disease (n=2438; HR, 0.58; 95% CI, 0.42 to 0.80). Statin use was not associated with an increase in malignancy, transaminase elevation, or rhabdomyolysis.Statin therapy in the setting of a very low LDL level appears to be safe and is associated with improved survival.
View details for DOI 10.1161/CIRCULATIONAHA.107.694117
View details for Web of Science ID 000248572300010
View details for PubMedID 17664373
Prognostic value of heart rate increase at onset of exercise testing
2007; 115 (4): 468-474
The initial response of heart rate to dynamic exercise has been proposed as having prognostic value in limited studies that have used modalities other than the treadmill. Our aim was to evaluate the prognostic value of early heart rate parameters in patients referred for routine clinical treadmill testing.The heart rate rise at the onset of exercise was measured in 1959 patients referred for clinical treadmill testing at the Palo Alto (Calif) Veterans Affairs Medical Center from 1997 to 2004. Multivariable Cox survival analysis was performed for 197 all-cause and 74 cardiovascular deaths that accrued during a mean follow-up of 5.4+/-2.1 years. Decreased heart rate changes at all initial relative exercise workloads were associated with significantly increased all-cause mortality. The heart rate rise at one-third total exercise capacity, however, was the only early heart rate variable that significantly predicted both all-cause and cardiovascular risk after adjustment for confounders. Failing to reach 1 SD in the heart rate rise at one-third total exercise capacity was associated with a 28% increased all-cause mortality rate (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001) and a 35% cardiovascular mortality rate (hazard ratio, 0.65; 95% CI, 0.49 to 0.86; P=0.003). Of all heart rate measurements considered (initial and recovery), the heart rate increase at peak exercise was the most powerful predictor of cardiovascular prognosis after adjustment for potential confounders. The Duke treadmill score, however, was superior to all heart rate measurements in the prediction of cardiovascular mortality.In the present study population, a rapid initial heart rate rise was associated with improved survival, but the heart rate increase at peak exercise and other conventional measurements such as exercise capacity and the Duke treadmill score were more powerful predictors of prognosis.
View details for DOI 10.1161/CIRCULATIONAHA.106.666388
View details for Web of Science ID 000243853400010
View details for PubMedID 17242274
One surprise after another
NEW ENGLAND JOURNAL OF MEDICINE
2005; 352 (14): 1474-1479
View details for Web of Science ID 000228145200012
Cloning of a unique lipase from endothelial cells extends the lipase gene family
JOURNAL OF BIOLOGICAL CHEMISTRY
1999; 274 (20): 14170-14175
A new lipoprotein lipase-like gene has been cloned from endothelial cells through a subtraction methodology aimed at characterizing genes that are expressed with in vitro differentiation of this cell type. The conceptual endothelial cell-derived lipase protein contains 500 amino acids, including an 18-amino acid hydrophobic signal sequence, and is 44% identical to lipoprotein lipase and 41% identical to hepatic lipase. Comparison of primary sequence to that of lipoprotein and hepatic lipase reveals conservation of the serine, aspartic acid, and histidine catalytic residues as well as the 10 cysteine residues involved in disulfide bond formation. Expression was identified in cultured human umbilical vein endothelial cells, human coronary artery endothelial cells, and murine endothelial-like yolk sac cells by Northern blot. In addition, Northern blot and in situ hybridization analysis revealed expression of the endothelial-derived lipase in placenta, liver, lung, ovary, thyroid gland, and testis. A c-Myc-tagged protein secreted from transfected COS7 cells had phospholipase A1 activity but no triglyceride lipase activity. Its tissue-restricted pattern of expression and its ability to be expressed by endothelial cells, suggests that endothelial cell-derived lipase may have unique functions in lipoprotein metabolism and in vascular disease.
View details for Web of Science ID 000080322200064
View details for PubMedID 10318835
Proton pump inhibitors and vascular function: A prospective cross-over pilot study
2015; 20 (4): 309-316
Proton pump inhibitors (PPIs) are commonly used drugs for the treatment of gastric reflux. Recent retrospective cohorts and large database studies have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm. We conducted a controlled, open-label, cross-over pilot study among 21 adults aged 18 and older who are healthy (n=11) or have established clinical cardiovascular disease (n=10). Study subjects were assigned to receive a PPI (Prevacid; 30 mg) or a placebo pill once daily for 4 weeks. After a 2-week washout period, participants were crossed over to receive the alternate treatment for the ensuing 4 weeks. Subjects underwent evaluation of vascular function (by the EndoPAT technique) and had plasma levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk) measured prior to and after each treatment interval. We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA (r = -0.364). Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo, and this trend was more pronounced amongst those subjects with a history of vascular disease. However, these trends did not reach statistical significance, and PPI use was also not associated with an impairment in flow-mediated vasodilation during the course of this study. In conclusion, in this open-label, cross-over pilot study conducted among healthy subjects and coronary disease patients, PPI use did not significantly influence vascular endothelial function. Larger, long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has recently been reported in retrospective cohort studies.
View details for DOI 10.1177/1358863X14568444
View details for Web of Science ID 000359414300001
- Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population PLOS ONE 2015; 10 (6)
Improved Reclassification of Mortality Risk by Assessment of Physical Activity in Patients Referred for Exercise Testing
AMERICAN JOURNAL OF MEDICINE
2015; 128 (4): 396-402
Inability to meet minimal guidelines on physical activity is associated with poor health outcomes, but quantifying activity can be complex. We studied whether a simple question regarding participation in regular activity improves risk classification for all-cause mortality.Maximal exercise testing was performed in 6962 patients (mean age, 58.9 ± 11 years) for clinical reasons. Subjects also were assessed for participation in regular activity using a simple yes/no response to meeting minimal recommendations on activity. The incremental value of adding a simple physical activity assessment to clinical, demographic, and exercise test information to predict mortality was determined using Cox proportional hazards models, net reclassification improvement, and integrated discrimination index during a mean follow-up of 9.7 ± 4 years.Subjects who did not meet the minimal guidelines on activity had a lower exercise capacity (7.4 ± 4.3 vs 9.1 ± 3.6 metabolic equivalents, P < .0001) and a higher annual mortality rate (2.42% vs 1.71%, P < .001). Not meeting activity guidelines was associated with an age-adjusted 36% higher risk of mortality (hazard ratio, 1.36; 95% confidence interval, 1.22-1.51, P < .0001). Among clinical and exercise test variables, fitness had the highest C-index for predicting mortality (0.72, P < .001). The addition of physical activity classification to a model including traditional risk factors resulted in a net reclassification improvement of 22.8% (P < .001); adding fitness to the traditional risk factor model resulted in a net reclassification improvement of 43.5% (P < .001).The addition of a simple assessment of physical activity status significantly improves reclassification of risk for all-cause mortality among patients who are referred for exercise testing.
View details for DOI 10.1016/j.amjmed.2014.10.061
View details for Web of Science ID 000351365600029
View details for PubMedID 25511076
Effect of Physical Activity Assessment on Prognostication for Peripheral Artery Disease and Mortality
MAYO CLINIC PROCEEDINGS
2015; 90 (3): 339-345
To examine whether a simple question about the performance of regular vigorous activity is associated with peripheral artery disease (PAD) and mortality.A total of 1288 individuals undergoing nonemergency coronary angiography were assessed for participation in regular vigorous activity by questionnaire. Data on demographic characteristics, ankle-brachial indexes, and cardiovascular outcomes were prospectively collected.Compared with those who denied participation in regular vigorous activity, those who reported participation were less likely to have PAD (odds ratio, 0.58; 95% CI, 0.39-0.86), had higher ankle-brachial indexes, had better Walking Impairment Questionnaire scores (P<.001), and experienced reduced all-cause mortality rates (hazard ratio, 0.48; 95% CI, 0.31-0.74). When added to the Framingham Risk Score, the response improved the net reclassification index for all-cause (32.6%) and cardiovascular (32.0%) mortality.Among at-risk individuals, regular vigorous activity is associated with decreased PAD and all-cause mortality. Simple and readily available, a single yes/no query about participation in regular vigorous exercise could be used to improve risk stratification.
View details for DOI 10.1016/j.mayocp.2014.12.016
View details for Web of Science ID 000350588500007
- Rationale and Design for PACE: Patients with Intermittent Claudication Injected with ALDH Bright Cells AMERICAN HEART JOURNAL 2014; 168 (5): 667-673
Rationale and design for PACE: patients with intermittent claudication injected with ALDH bright cells.
American heart journal
2014; 168 (5): 667-673
Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in patients with PAD, have limitations. Cells identified using cytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network to assess the safety and efficacy of autologous bone marrow-derived ALDH(br) cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index less than 0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary end points are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance imaging at 6 months compared with baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging-based end points that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDH(br) cells in patients with claudication and provide valuable insight into the utility of advanced magnetic resonance imaging end points.
View details for DOI 10.1016/j.ahj.2014.07.021
View details for PubMedID 25440794
- Clinical and socioeconomic factors associated with unrecognized peripheral artery disease VASCULAR MEDICINE 2014; 19 (4): 289-296
Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation.
2014; 10 (3)
Genome-wide association studies (GWAS) have identified chromosomal loci that affect risk of coronary heart disease (CHD) independent of classical risk factors. One such association signal has been identified at 6q23.2 in both Caucasians and East Asians. The lead CHD-associated polymorphism in this region, rs12190287, resides in the 3' untranslated region (3'-UTR) of TCF21, a basic-helix-loop-helix transcription factor, and is predicted to alter the seed binding sequence for miR-224. Allelic imbalance studies in circulating leukocytes and human coronary artery smooth muscle cells (HCASMC) showed significant imbalance of the TCF21 transcript that correlated with genotype at rs12190287, consistent with this variant contributing to allele-specific expression differences. 3' UTR reporter gene transfection studies in HCASMC showed that the disease-associated C allele has reduced expression compared to the protective G allele. Kinetic analyses in vitro revealed faster RNA-RNA complex formation and greater binding of miR-224 with the TCF21 C allelic transcript. In addition, in vitro probing with Pb2+ and RNase T1 revealed structural differences between the TCF21 variants in proximity of the rs12190287 variant, which are predicted to provide greater access to the C allele for miR-224 binding. miR-224 and TCF21 expression levels were anti-correlated in HCASMC, and miR-224 modulates the transcriptional response of TCF21 to transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF) signaling in an allele-specific manner. Lastly, miR-224 and TCF21 were localized in human coronary artery lesions and anti-correlated during atherosclerosis. Together, these data suggest that miR-224 interaction with the TCF21 transcript contributes to allelic imbalance of this gene, thus partly explaining the genetic risk for coronary heart disease associated at 6q23.2. These studies implicating rs12190287 in the miRNA-dependent regulation of TCF21, in conjunction with previous studies showing that this variant modulates transcriptional regulation through activator protein 1 (AP-1), suggests a unique bimodal level of complexity previously unreported for disease-associated variants.
View details for DOI 10.1371/journal.pgen.1004263
View details for PubMedID 24676100
- Coronary Heart Disease-Associated Variation in TCF21 Disrupts a miR-224 Binding Site and miRNA-Mediated Regulation PLOS GENETICS 2014; 10 (3)
- Self-Reported History of Childhood Smoking Is Associated with an Increased Risk for Peripheral Arterial Disease Independent of Lifetime Smoking Burden PLOS ONE 2014; 9 (2)
The combination of 9p21.3 genotype and biomarker profile improves a peripheral artery disease risk prediction model
2014; 19 (1): 3-8
Peripheral artery disease (PAD) is a highly morbid condition affecting more than 8 million Americans. Frequently, PAD patients are unrecognized and therefore do not receive appropriate therapies. Therefore, new methods to identify PAD have been pursued, but have thus far had only modest success. Here we describe a new approach combining genomic and metabolic information to enhance the diagnosis of PAD. We measured the genotype of the chromosome 9p21 cardiovascular-risk polymorphism rs10757269 as well as the biomarkers C-reactive protein, cystatin C, β2-microglobulin, and plasma glucose in a study population of 393 patients undergoing coronary angiography. The rs10757269 allele was associated with PAD status (ankle-brachial index < 0.9) independent of biomarkers and traditional cardiovascular risk factors (odds ratio=1.92; 95% confidence interval, 1.29-2.85). Importantly, compared to a previously validated risk factor-based PAD prediction model, the addition of biomarkers and rs10757269 significantly and incrementally improved PAD risk prediction as assessed by the net reclassification index (NRI=33.5%; p=0.001) and integrated discrimination improvement (IDI=0.016; p=0.017). In conclusion, a model including a panel of biomarkers, which includes both genomic information (which is reflective of heritable risk) and metabolic information (which integrates environmental exposures), predicts the presence or absence of PAD better than established risk models, suggesting clinical utility for the diagnosis of PAD.
View details for DOI 10.1177/1358863X13514791
View details for Web of Science ID 000337579400001
Self-reported history of childhood smoking is associated with an increased risk for peripheral arterial disease independent of lifetime smoking burden.
2014; 9 (2)
Atherosclerotic disorders are well known to be associated with obesity, lipid profile, smoking, hypertension and other medical comorbidities, and large cohort studies have explored the childhood correlates to these adult risk factors. However, there has been little investigation into the childhood risk factors for peripheral arterial disease (PAD). We endeavored to better understand the role of smoking in childhood in the risk for PAD in a well described cohort of 1,537 adults at high risk for cardiovascular disease. In a multivariate regression model, we observed an increased risk of PAD among those who reported a history of smoking during childhood (OR = 2.86; 95% CI, 1.99-4.11; P<0.001), which remained statistically significant after controlling for lifetime smoking burden (OR = 1.55; 95% CI, 1.00-2.41; P = 0.049). Our novel observation of disproportionate risk of PAD conferred by a history of childhood smoking may reflect an unrecognized biological mechanism such as a unique susceptibility to vascular injury or an unaccounted for covariate such as secondhand smoke exposure in childhood. This observation suggests further investigation is required into the pathophysiology of smoking in the developing vasculature and the need for detailed clinical data about patterns of childhood smoking and smoke exposure.
View details for DOI 10.1371/journal.pone.0088972
View details for PubMedID 24558458
Association of lower extremity performance with cardiovascular and all-cause mortality in patients with peripheral artery disease: a systematic review and meta-analysis.
Journal of the American Heart Association
2014; 3 (4)
Peripheral artery disease (PAD) is associated with impaired mobility and a high rate of mortality. The aim of this systematic review was to investigate whether reduced lower extremity performance was associated with an increased incidence of cardiovascular and all-cause mortality in people with PAD.A systematic search of the MEDLINE, EMBASE, SCOPUS, Web of Science, and Cochrane Library databases was conducted. Studies assessing the association between measures of lower extremity performance and cardiovascular or all-cause mortality in PAD patients were included. A meta-analysis was conducted combining data from commonly assessed performance tests. The 10 identified studies assessed lower extremity performance by strength tests, treadmill walking performance, 6-minute walk, walking velocity, and walking impairment questionnaire (WIQ). A meta-analysis revealed that shorter maximum walking distance was associated with increased 5-year cardiovascular (unadjusted RR=2.54, 95% CI 1.86 to 3.47, P<10(-5), n=1577, fixed effects) and all-cause mortality (unadjusted RR=2.23 95% CI 1.85 to 2.69, P<10(-5), n=1710, fixed effects). Slower 4-metre walking velocity, a lower WIQ stair-climbing score, and poor hip extension, knee flexion, and plantar flexion strength were also associated with increased mortality. No significant associations were found for hip flexion strength, WIQ distance score, or WIQ speed score with mortality.A number of lower extremity performance measures are prognostic markers for mortality in PAD and may be useful clinical tools for identifying patients at higher risk of death. Further studies are needed to determine whether interventions that improve measures of lower extremity performance reduce mortality.
View details for DOI 10.1161/JAHA.114.001105
View details for PubMedID 25122666
- Disease-Related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of TCF21 Expression at the 6q23.2 Coronary Heart Disease Locus PLOS GENETICS 2013; 9 (7)
A hybrid genomic and proteomic biomarker panel accurately predicts peripheral arterial disease status
SAGE PUBLICATIONS LTD. 2013: 165-165
View details for Web of Science ID 000319606800035
Walking Impairment Questionnaire Improves Mortality Risk Prediction Models in a High-Risk Cohort Independent of Peripheral Arterial Disease Status
CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES
2013; 6 (3): 255-261
Background- The Walking Impairment Questionnaire (WIQ) is a subjective measure of patient-reported walking performance developed for peripheral arterial disease. The purpose of this study is to examine whether this simple tool can improve the predictive capacity of established risk models and whether the WIQ can be used in patients without peripheral arterial disease. Methods and Results- At baseline we assessed the walking distance, stair-climbing, and walking speed WIQ category scores among individuals who were undergoing coronary angiography. During a median follow-up of 5.0 years, there were 172 mortalities among 1417 study participants. Adjusted Cox proportional hazards models showed that all 3 WIQ categories independently predicted future all-cause and cardiovascular mortality, including among individuals without peripheral arterial disease (P<0.001). Compared with the cardiovascular risk factors model, we observed significantly increased risk discrimination with a C-index of 0.741 (change in C-index, 0.040; 95% confidence interval, 0.011-0.068) and 0.832 (change in C-index, 0.080; 95% confidence interval, 0.034-0.126) for all-cause and cardiovascular mortality, respectively. Examination of risk reclassification using the net reclassification improvement index showed a 48.4% (P<0.001) improvement for all-cause mortality and a 77.4% (P<0.001) improvement for cardiovascular mortality compared with the cardiovascular risk factors model. Conclusions- All 3 WIQ categories independently predicted future all-cause and cardiovascular mortality. Importantly, we found that this subjective measure of walking ability could be extended to patients without peripheral arterial disease. The addition of the WIQ scores to established cardiovascular risk models significantly improved risk discrimination and reclassification, suggesting broad clinical use for this simple, inexpensive test.
View details for DOI 10.1161/CIRCOUTCOMES.111.000070
View details for Web of Science ID 000319392600005
View details for PubMedID 23633217
Usefulness of the Addition of Beta-2-Microglobulin, Cystatin C and C-Reactive Protein to an Established Risk Factors Model to Improve Mortality Risk Prediction in Patients Undergoing Coronary Angiography
AMERICAN JOURNAL OF CARDIOLOGY
2013; 111 (6): 851-856
Evidence-based therapies are available to reduce the risk for death from cardiovascular disease, yet many patients go untreated. Novel methods are needed to identify those at highest risk for cardiovascular death. In this study, the biomarkers β2-microglobulin, cystatin C, and C-reactive protein were measured at baseline in a cohort of participants who underwent coronary angiography. Adjusted Cox proportional-hazards models were used to determine whether the biomarkers predicted all-cause and cardiovascular mortality. Additionally, improvements in risk reclassification and discrimination were evaluated by calculating the net reclassification improvement, C-index, and integrated discrimination improvement with the addition of the biomarkers to a baseline model of risk factors for cardiovascular disease and death. During a median follow-up period of 5.6 years, there were 78 deaths among 470 participants. All biomarkers independently predicted future all-cause and cardiovascular mortality. A significant improvement in risk reclassification was observed for all-cause (net reclassification improvement 35.8%, p = 0.004) and cardiovascular (net reclassification improvement 61.9%, p = 0.008) mortality compared to the baseline risk factors model. Additionally, there was significantly increased risk discrimination with C-indexes of 0.777 (change in C-index 0.057, 95% confidence interval 0.016 to 0.097) and 0.826 (change in C-index 0.071, 95% confidence interval 0.010 to 0.133) for all-cause and cardiovascular mortality, respectively. Improvements in risk discrimination were further supported using the integrated discrimination improvement index. In conclusion, this study provides evidence that β2-microglobulin, cystatin C, and C-reactive protein predict mortality and improve risk reclassification and discrimination for a high-risk cohort of patients who undergo coronary angiography.
View details for DOI 10.1016/j.amjcard.2012.11.055
View details for Web of Science ID 000316537700013
View details for PubMedID 23290308
AN ALTERNATIVE ANKLE-BRACHIAL INDEX METHOD IDENTIFIES INDIVIDUALS AT HIGH-RISK FOR CARDIOVASCULAR MORTALITY THAT ARE CURRENTLY OVERLOOKED
ELSEVIER SCIENCE INC. 2013: E2124-E2124
View details for Web of Science ID 000316555202328
Exercise capacity is the strongest predictor of mortality in patients with peripheral arterial disease
JOURNAL OF VASCULAR SURGERY
2013; 57 (3): 728-733
The objective of this study was to assess the predictive value of clinical and exercise test variables in patients with peripheral arterial disease (PAD).A customized symptom-limited ramp treadmill protocol was used to assess 725 PAD patients referred for exercise testing at the Palo Alto Veterans Hospital between 1997 and 2011. Detailed clinical and exercise test data were collected at baseline, and patients were followed up for a mean of 11.3 ± 6.3 years.During follow-up, there were 364 deaths. Baseline exercise capacity was 7.0 ± 2.6 metabolic equivalents (METs) among survivors and 5.5 ± 2.4 METs in those who died (P < .001). Although several physiologic parameters differed between survivors and nonsurvivors, age-adjusted Cox regression revealed that exercise capacity was the strongest independent predictor of death. Each additional MET achieved was associated with age-adjusted 18% and 20% reductions in all-cause and cardiovascular mortality, respectively (P < .001 for both). This variable surpassed all classical risk factors (including smoking and history of congestive heart failure) and all measured exercise test responses (including symptoms and electrocardiograph abnormalities).Among PAD patients, reduced exercise capacity is the most powerful harbinger of long-term mortality. This factor has predictive power beyond traditional risk factors and confirms the critical importance of fitness in this cohort.
View details for DOI 10.1016/j.jvs.2012.07.051
View details for Web of Science ID 000315944400019
View details for PubMedID 23044259
Disease-related growth factor and embryonic signaling pathways modulate an enhancer of TCF21 expression at the 6q23.2 coronary heart disease locus.
2013; 9 (7)
Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-β) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.
View details for DOI 10.1371/journal.pgen.1003652
View details for PubMedID 23874238
Network analysis of unstructured EHR data for clinical research.
AMIA Summits on Translational Science proceedings AMIA Summit on Translational Science
2013; 2013: 14-18
In biomedical research, network analysis provides a conceptual framework for interpreting data from high-throughput experiments. For example, protein-protein interaction networks have been successfully used to identify candidate disease genes. Recently, advances in clinical text processing and the increasing availability of clinical data have enabled analogous analyses on data from electronic medical records. We constructed networks of diseases, drugs, medical devices and procedures using concepts recognized in clinical notes from the Stanford clinical data warehouse. We demonstrate the use of the resulting networks for clinical research informatics in two ways-cohort construction and outcomes analysis-by examining the safety of cilostazol in peripheral artery disease patients as a use case. We show that the network-based approaches can be used for constructing patient cohorts as well as for analyzing differences in outcomes by comparing with standard methods, and discuss the advantages offered by network-based approaches.
View details for PubMedID 24303229
- Loss of CDKN2B Promotes p53-Dependent Smooth Muscle Cell Apoptosis and Aneurysm Formation ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 2013; 33 (1): E1-?
Practice-based evidence: profiling the safety of cilostazol by text-mining of clinical notes.
2013; 8 (5)
Peripheral arterial disease (PAD) is a growing problem with few available therapies. Cilostazol is the only FDA-approved medication with a class I indication for intermittent claudication, but carries a black box warning due to concerns for increased cardiovascular mortality. To assess the validity of this black box warning, we employed a novel text-analytics pipeline to quantify the adverse events associated with Cilostazol use in a clinical setting, including patients with congestive heart failure (CHF).We analyzed the electronic medical records of 1.8 million subjects from the Stanford clinical data warehouse spanning 18 years using a novel text-mining/statistical analytics pipeline. We identified 232 PAD patients taking Cilostazol and created a control group of 1,160 PAD patients not taking this drug using 1∶5 propensity-score matching. Over a mean follow up of 4.2 years, we observed no association between Cilostazol use and any major adverse cardiovascular event including stroke (OR = 1.13, CI [0.82, 1.55]), myocardial infarction (OR = 1.00, CI [0.71, 1.39]), or death (OR = 0.86, CI [0.63, 1.18]). Cilostazol was not associated with an increase in any arrhythmic complication. We also identified a subset of CHF patients who were prescribed Cilostazol despite its black box warning, and found that it did not increase mortality in this high-risk group of patients.This proof of principle study shows the potential of text-analytics to mine clinical data warehouses to uncover 'natural experiments' such as the use of Cilostazol in CHF patients. We envision this method will have broad applications for examining difficult to test clinical hypotheses and to aid in post-marketing drug safety surveillance. Moreover, our observations argue for a prospective study to examine the validity of a drug safety warning that may be unnecessarily limiting the use of an efficacious therapy.
View details for DOI 10.1371/journal.pone.0063499
View details for PubMedID 23717437
Exercise capacity is the strongest predictor of mortality in patients with peripheral arterial disease
SAGE PUBLICATIONS LTD. 2012: 204-205
View details for Web of Science ID 000304719900029
The Effect of Angiotensin-Converting Enzyme Inhibitors and Statins on the Progression of Aortic Sclerosis and Mortality
JOURNAL OF HEART VALVE DISEASE
2012; 21 (3): 337-343
Although aortic sclerosis has been associated with an increase in adverse cardiovascular outcomes, no proven therapy has been shown to slow its progression to overt aortic stenosis (AS). Thus, the hypothesis was assessed that treatment with angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs) or statins may be associated with an improvement in the clinical outcome of these patients.A total of 4,105 patients with evidence of aortic sclerosis seen on transthoracic echocardiography (defined as thickening or calcification with a mean valve gradient < or = 15 mmHg) was identified. Patients with a sclerotic valve who were treated with ACE-Is/ARBs or statins were followed for a mean period of 1,078 +/- 615 days. After adjustment for the propensity to receive ACE-Is/ARBs or statins, mortality, hemodynamic progression to AS, hospitalization for ischemic heart disease (IHD), and congestive heart failure (CHF) were assessed and related to the medical treatment.At baseline, patients with aortic sclerosis who were treated with an ACE-I/ARB or a statin suffered significantly more from comorbidities such as IHD, CHF, hypertension, diabetes, and peripheral arterial disease, when compared to subjects with sclerotic valves not treated with these drugs. After adjustment for confounding factors, treatment with statins was associated with a significant reduction in mortality (odds ratio [OR] 0.73, 95% CI 0.56-0.98, p = 0.001), admission for IHD (OR 0.81, 95% CI 0.66-0.99, p = 0.03), admission for CHF (OR 0.68, 95% CI 0.55-0.85, p = 0.01) and progression to AS (OR 0.64, 95% CI 0.42-0.97, p = 0.03). While ACE-I treatment resulted in a significant reduction in admission for IHD (OR 0.80, 95% CI 0.65-0.98, p = 0.03) and CHF (OR 0.76, 95% CI 0.62-0.94, p = 0.01), the beneficial trend towards reduced mortality and delayed progression to AS was not significant.Treatment of this patient population with statins led to a significant reduction in mortality and also slowed the progression to AS--an effect that was not statistically significant with ACE-I treatment.
View details for Web of Science ID 000306675500011
View details for PubMedID 22808835
Network Analysis Identifies the Orphan Receptor Tyrosine Kinase Ros1 as a Determinant of Glutathione Peroxidase-1 Mediated Vascular Remodeling
LIPPINCOTT WILLIAMS & WILKINS. 2011
View details for Web of Science ID 000299738703092
Microrna-21 Regulates Expansion of Abdominal Aortic Aneurysms Through the PTEN/PI3K/AKT Pathway
LIPPINCOTT WILLIAMS & WILKINS. 2011
View details for Web of Science ID 000299738707282
- Two Decades of Progress in Vascular Medicine AMERICAN JOURNAL OF MEDICINE 2011; 124 (9): 791-792
CDKN2B Regulates Cell Fate Decisions in Human Vascular Smooth Muscle Cells
LIPPINCOTT WILLIAMS & WILKINS. 2010
View details for Web of Science ID 000208231602363
The Role of CDKN2B in Vascular Disease
LIPPINCOTT WILLIAMS & WILKINS. 2010
View details for Web of Science ID 000208231602980
Microarray Analysis Identifies miRNA-26a as a Regulator of Vascular Smooth Muscle Cell Phenotypic Modulation
LIPPINCOTT WILLIAMS & WILKINS. 2010: E244-E244
View details for Web of Science ID 000283234800283
Endogenous regulation of cardiovascular function by apelin-APJ
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
2009; 297 (5): H1904-H1913
Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.
View details for DOI 10.1152/ajpheart.00686.2009
View details for Web of Science ID 000271143400045
View details for PubMedID 19767528
- Response to letter regarding article, "Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival" CIRCULATION 2008; 117 (9): E175-E175
Clinical significance of high-density lipoprotein cholesterol in patients with low low-density lipoprotein cholesterol
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2008; 51 (1): 49-55
We sought to evaluate the significance of high-density lipoprotein cholesterol (HDL-C) in the context of low low-density lipoprotein cholesterol (LDL-C).Earlier studies support an inverse correlation between circulating HDL-C and coronary risk in patients with normal or elevated LDL-C.This study involved 4,188 patients attending the Palo Alto Veterans Administration Medical Center or affiliated clinics with LDL-C levels below 60 mg/dl. Outcomes were examined 1 year after the index LDL-C date. The combined primary end point was myocardial injury or hospitalization from ischemic heart disease. The secondary end point was all-cause mortality.Mean HDL-C levels (mg/dl) by quartile (Q) were: Q1 28 mg/dl, Q2 36 mg/dl, Q3 43 mg/dl, and Q4 63 mg/dl. The rate of myocardial injury or hospitalization for ischemic heart disease showed an inverse relationship to HDL-C (adjusted odds ratios: Q1 1.59 [95% confidence interval (CI) 1.16 to 2.19], Q2 1.39 [95% CI 1.01 to 1.92], Q3 1.33 [95% CI 0.96 to 1.84], and Q4 reference) that persisted regardless of statin use or recent myocardial injury. Analyzing HDL-C as a continuous variable revealed a 10% [95% CI 3% to 17%] increase in the combined end point of myocardial injury or hospitalization for ischemic heart disease for every 10-mg/dl decrease in HDL-C. The unadjusted and adjusted incidence of all-cause mortality demonstrated a U-shaped relationship to HDL-C (adjusted odds ratios: Q1 1.13 [95% CI 0.79 to 1.62], Q2 0.97 [95% CI 0.67 to 1.40], Q3 0.74 [95% CI 0.50 to 1.09], and Q4 reference).The inverse relationship between HDL-C and coronary risk persists even among patients with LDL-C below 60 mg/dl, although a U-shaped relationship is observed between HDL-C and all-cause mortality.
View details for DOI 10.1016/j.jacc.2007.07.086
View details for Web of Science ID 000252510300008
View details for PubMedID 18174036
Clinical dilemmas in treating left ventricular thrombus.
International journal of cardiology
2007; 114 (3): e118-9
View details for PubMedID 17049652
Right coronary cameral fistula resulting from surgery of double chamber right ventricle.
Journal of the American Society of Echocardiography
2006; 19 (9): 1191 e9-11
View details for PubMedID 16950481
The effect of preoperative statin therapy on cardiovascular outcomes in patients undergoing infrainguinal vascular surgery
INTERNATIONAL JOURNAL OF CARDIOLOGY
2005; 104 (3): 264-268
Patients undergoing vascular surgery are at increased risk for perioperative cardiovascular (CV) complications. Our goal was to determine the effect of preoperative statin therapy on perioperative cardiac and vascular outcomes, and long-term survival in patients undergoing infrainguinal vascular bypass surgery.We retrospectively reviewed consecutive infrainguinal vascular bypass surgeries on 446 patients performed between 1995-2001 at the University of Chicago Medical Center. Information was collected on preoperative statin and beta-blocker use, baseline characteristics, perioperative cardiac and major vascular complications, and length of stay (LOS). Long-term survival was assessed using the Social Security Death Index (SSDI).Thirty day perioperative complications included all-cause mortality (2.5%), CV mortality (1.8%), myocardial infarction (MI) (4.7%), stroke (1.1%), and major peripheral vascular complications (12.8%), and the composite of cardiac and vascular complications [combined CV complications] (17.9%). Statin therapy was associated with fewer combined CV complications (6.9% vs 20.1%, p=0.008), and a shorter LOS (6.4 vs 9.7 days, p=0.007). On multivariate logistic regression analysis, adjusting for significant baseline characteristics including beta-blocker use, statin therapy was independently associated fewer combined CV complications (odds ratio (OR) 0.36, 95% confidence interval (CI) 0.14-0.93, p=0.035) and a shorter LOS (OR 1.49, 95% CI 1.14-1.95, p=0.003). In a mean follow up period of 5.5 years, 215 deaths (48%) occurred. Statin therapy was independently associated with improved long-term survival (OR 0.52, 95% CI 0.32-0.84, p<0.004), after adjusting for significant baseline characteristics.Preoperative statin therapy is associated with fewer combined perioperative cardiac and major vascular complications, a shorter length of stay, and improved long-term survival in patients undergoing infrainguinal vascular bypass surgery.
View details for DOI 10.1016/j.ijcard.2004.10.030
View details for Web of Science ID 000232752700004
View details for PubMedID 16186054
Interleukin-6 causes endothelial barrier dysfunction via the protein kinase C pathway
ACADEMIC PRESS INC ELSEVIER SCIENCE. 2002: 118-123
Elevated levels of interleukin-6 (IL-6) have been identified in a variety of systemic inflammatory states that are associated with endothelial barrier dysfunction, but the specific effect of IL-6 on endothelial permeability and the mechanism of action have not been fully examined. The current study evaluated the effect of IL-6 on endothelial permeability and on the distribution of the tight junctional protein ZO-1 and cytoskeletal actin. We also assessed the role of protein kinase C (PKC) in this process.Confluent monolayers of human umbilical vein endothelial cells (n = 6) were exposed to IL-6 (50-500 ng/ml) in the presence or absence of the PKC inhibitor Gö6976 (0.1 microM). Transendothelial electrical resistance (TEER) was measured at the onset of exposure and at 6-h intervals and compared with that of control cells using ANOVA with a Bonferroni multiple comparison test. Additional monolayers were exposed to IL-6, stained for ZO-1 and F-actin, and evaluated via fluorescence microscopy.Interleukin-6 increased endothelial permeability as measured by TEER in a dose- and time-dependent manner. In the presence of PKC inhibitor, the IL-6-mediated increase in permeability was attenuated (18-h TEER 73% of control with IL-6 exposure vs 95% of control with IL-6 + Gö6976 inhibitor, P < 0.01). Microscopy revealed that permeability changes were accompanied by a redistribution of the tight junctional protein ZO-1 and cytoskeletal actin, increased cell contraction, and disorganization of the intercellular borders. Conclusions. The inflammatory cytokine IL-6 is an important mediator of increased endothelial permeability via alterations in the ultrastructural distribution of tight junctions and morphologic changes in cell shape. PKC is a critical intracellular messenger in these IL-6-mediated changes. A better understanding of this mechanism should allow the determination of rational treatment strategies for endothelial barrier dysfunction which occurs in inflammatory states.
View details for DOI 10.1006/jsre.2002.6415
View details for Web of Science ID 000176074300008
View details for PubMedID 12020130
Gender does not influence outcomes after iliac angioplasty
ELSEVIER SCIENCE INC. 2002: 55-60
The current study was undertaken to evaluate the potential influence of gender on iliac angioplasty outcomes. All iliac angioplasty procedures performed at a tertiary care center from 1994 to 1999 were reviewed. One hundred four angioplasties with or without stenting were performed in 44 women (56 limbs) and 40 men (48 limbs). Age and atherosclerotic risk factors were similar in men and women. Iliac angioplasty was performed for limb salvage in 41% of patients (39% female vs. 44% male; p = 0.65). There were no differences in degree of stenosis, lesion length, or initial angioplasty site. Female iliac arteries were more likely to be occluded (21% vs. 6%; p = 0.03); mean iliac artery luminal diameter was smaller in women than in men (6.5 +/- 0.5 mm vs. 8.2 +/- 0.6 mm; p < 0.001). After a median follow-up of 13 months, there were no significant differences in 2-year primary patency, endovascular primary-assisted patency, or limb salvage rates between women and men. Despite having smaller iliac arteries and a higher incidence of arterial occlusion before treatment, women had outcomes similar to those of men after iliac angioplasty. The current results support the initial use of angioplasty to treat common and external iliac artery occlusive disease in both women and men.
View details for DOI 10.1007/s10016-001-0131-7
View details for Web of Science ID 000174307700010
View details for PubMedID 11904805
Regulated expression of a unique lipase in endothelial cells suggests a local role in disease-associated lipid metabolism in the blood vessel wall
LIPPINCOTT WILLIAMS & WILKINS. 1999: 610-610
View details for Web of Science ID 000083417103209
Tetracycline-regulatable expression vectors tightly regulate in vitro gene expression of secreted proteins
1998; 221 (2): 279-285
The regulation of gene expression by the tetracycline system has attracted a high level of interest in the recent past. However, expression of secreted proteins has not been evaluated precisely. In this study, we constructed two versions of a one-plasmid system containing the elements necessary for the regulation of gene expression. The regulatable elements and the selectable marker (Neor) were set up in two different configurations, pTRIN31 and pTRIN76. With these two regulatable versions, the levels of protein expression after transfection into the NIH/3T3 cell line were measured by insertion of three different genes encoding the secreted proteins (hGH, ApoE3, hGM-CSF). The maximum levels of gene expression obtained with the pTRIN76-derived plasmids were 100ng/24h/106 cells for hGH, 427ng/24h/106 cells for ApoE3 and 108ng/24h/106 cells for hGM-CSF. For the pTRIN31-derived plasmids the maximum levels were 2.7ng/24h/106 cells for hGH and 47ng/24h/106 for ApoE3. Both plasmids give rise to an expression of the transfected gene that can be tightly regulated by three different molecules: tetracycline, minocycline and doxycycline. The levels of the secreted proteins are below the detectable level when the reporter genes are repressed. This repression is reversible within 48h after the regulator has been removed from the medium.
View details for Web of Science ID 000077027300013
View details for PubMedID 9795241