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Biomedical subjects

Daniel I Simon

Publications and source records attributed to Daniel I Simon.

At least 19 recordsLinked to original sources
PubMed2006

Effectiveness of same day percutaneous coronary intervention followed by minimally invasive aortic valve replacement for aortic stenosis and moderate coronary disease ("hybrid approach").

In 2005, the investigators described a "hybrid" cardiovascular interventional strategy combining percutaneous coronary intervention (PCI) for coronary artery disease (CAD) followed by valve surgery for patients with urgent complex CAD and valve disease to reduce morbidity and mortality. This hybrid approach has been extended prospectively in elderly, high-risk patients with aortic stenosis scheduled for elective minimally invasive aortic valve replacement (MI-AVR) who, on preoperative coronary angiography, were found to have moderate CAD amenable to PCI. In this prospective, observational series, 18 patients (mean age 76 years) underwent elective hybrid MI-AVR with PCI from May 2003 to February 2006. Five patients had undergone previous coronary artery bypass grafting. Patients underwent coronary angiography the day of (n = 12) or evening before (n = 6) MI-AVR, and after identifying moderately severe CAD, all 18 underwent the implantation of drug-eluting stents to the affected coronary arteries, followed by MI-AVR. Although all patients received standard doses of antiplatelet medications, including acetylsalicylic acid (325 mg before PCI and 325 mg/day thereafter) and clopidogrel (300 mg after PCI, 75 mg/day thereafter for 90 days for the Cypher stent), there were no reoperations for bleeding; only 8 of 18 patients required postoperative blood transfusions. One patient died postoperatively from a colonic perforation, and there were no late mortalities after a mean follow-up of 19 months. In conclusion, this hybrid strategy has low morbidity and mortality and may be a new therapeutic option for older, high-risk patients with combined CAD and aortic valve disease.

Aged↗
PubMed2006

Aspirin resistance or variable response or both?

Numerous clinical trials have demonstrated that aspirin is effective in secondary prevention and in high-risk primary prevention of adverse cardiovascular events. However, a constellation of clinical and laboratory evidence exists that demonstrates diminished or absent response to aspirin in some patients. This has led to the concept of "aspirin resistance," which is a poorly defined, somewhat misleading term. The mechanism for aspirin resistance has not been fully established, but it is almost certainly due to a combination of clinical, biological, and genetic properties affecting platelet function. There are no criteria for distinguishing true resistance from treatment failure, and there is no consensus on whether the definition of aspirin resistance should be based on clinical outcomes, laboratory evidence, or both. Studies in large populations are needed to define antiplatelet resistance using consistent and reproducible assays and correlate the measurements with clinical outcomes. One such prospective randomized trial is completed, and 2 others are under way: the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial compared clopidogrel and aspirin with placebo and aspirin for high-risk primary or secondary prevention, and the Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial (ASCET) is evaluating whether switching to clopidogrel will be superior to continued aspirin therapy in improving clinical outcomes in aspirin-resistant patients with angiographically documented coronary artery disease. The Research Evaluation to Study Individuals Who Show Thromboxane or P2Y(12) Receptor Resistance (RESISTOR) trial is investigating whether modifying antiplatelet regimens could prevent myonecrosis after percutaneous coronary intervention in patients with aspirin and clopidogrel resistance.

Aspirin↗
PubMed2006

Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events.

BACKGROUND: Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. METHODS AND RESULTS: We profiled platelet mRNA from patients with acute ST-segment-elevation myocardial infarction (STEMI, n=16) or stable coronary artery disease (n=44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated 1 candidate gene product by performing a prospective, nested case-control study (n=255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, P<0.001) and myeloid-related protein-14 (MRP-14; odds ratio 3.3, P=0.002). Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (17.0 versus 8.0 microg/mL, P<0.001). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (Ptrend<0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (P<0.001). Risks were independent of standard risk factors and C-reactive protein. CONCLUSIONS: The platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before STEMI, and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events.

Acute Disease↗
PubMed2006

Integrin signals, transcription factors, and monocyte differentiation.

The precise signals responsible for differentiation of circulating monocytes into tissue macrophages are incompletely defined. "Outside-in" integrin signaling has been implicated in modulating gene expression that affects cellular differentiation. This review highlights the role of transcription factors in monocyte differentiation and describes how integrin engagement orchestrates monocyte differentiation signals by regulating the expression of the forkhead transcription factor Foxp1, which functions as a transcriptional repressor of the macrophage colony-stimulating factor receptor c-fms. This represents a new pathway for integrin-dependent modulation of gene expression and control of cellular differentiation.

Cell Differentiation↗
PubMed2006

When size matters: lessons learned from left main stent embolization and retrieval.

While the advantages of drug-eluting stents (DES) have been demonstrated in moderate and small-sized vessels, the benefits of DES use in selected larger vessels are increasingly recognized. In the following case presentation, the use of a DES outside the approved vessel diameter to treat left main coronary artery disease led to retrograde migration of the stent over the guiding catheter. Solutions to capturing and retrieving a stent in this position are discussed and our approach to resolving the situation is presented.

Aged, 80 and over↗
PubMed2005

Increased neointima formation in cysteine-rich protein 2-deficient mice in response to vascular injury.

In response to arterial injury, medial vascular smooth muscle cells (VSMCs) proliferate and migrate into the intima, contributing to the development of occlusive vascular disease. The LIM protein cysteine-rich protein (CRP) 2 associates with the actin cytoskeleton and may maintain the cytoarchitecture. CRP2 also interacts with transcription factors in the nucleus to mediate SMC gene expression. To test the hypothesis that CRP2 may be an important regulator of vascular development or function we generated Csrp2 (gene symbol of the mouse CRP2 gene)-deficient (Csrp2(-/-)) mice by targeted mutation. Csrp2(-/-) mice did not have any gross vascular defects or altered expression levels of SM alpha-actin, SM22alpha, or calponin. Following femoral artery injury, CRP2 expression persisted in the vessel wall at 4 days and then decreased by 14 days. Intimal thickening was enhanced 3.4-fold in Csrp2(-/-) compared with wild-type (WT) mice 14 days following injury. Cellular proliferation was similar between WT and Csrp2(-/-) VSMC both in vivo and in vitro. Interestingly, Csrp2(-/-) VSMC migrated more rapidly in response to PDGF-BB and had increased Rac1 activation. Our data demonstrate that CRP2 is not required for vascular development. However, an absence of CRP2 enhanced VSMC migration and increased neointima formation following arterial injury.

Animals↗
PubMed2005

Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac-1 is critical for the biological response to vascular injury.

BACKGROUND: Leukocyte-platelet interactions are critical in the initiation and progression of atherosclerosis as well as restenosis. Although the leukocyte integrin Mac-1 (alphaMbeta2, CD11b/CD18) has been implicated in the firm adhesion and transmigration of leukocytes at sites of platelet deposition, the precise alphaMbeta2 counterligand responsible for mediating adhesion-strengthening interactions between neutrophils and platelets in vivo has not previously been identified. METHODS AND RESULTS: Our previous studies have established the P201-K217 sequence in the alphaMI domain as the binding site for platelet glycoprotein (GP) Ibalpha. Here we report that antibody targeting of alphaM(P201-K217) reduced alphaMbeta2-dependent adhesion to GP Ibalpha but not other alphaMbeta2 ligands, including fibrinogen, intercellular adhesion molecule-1, and junctional adhesion molecule-3. Anti-alphaM(P201-K217) inhibited the firm adhesion of both human and murine leukocytes to adherent platelets under laminar flow conditions. In a mouse femoral artery wire injury model, antibody targeting of alphaM(P201-K217) reduced leukocyte accumulation after injury that was accompanied by inhibition of cellular proliferation and neointimal thickening. CONCLUSIONS: This study demonstrates that GP Ibalpha is a physiologically relevant ligand for alphaMbeta2 and that integrin engagement of GP Ibalpha is critical to leukocyte function and the biological response to vascular injury. These observations establish a molecular target for selectively disrupting leukocyte-platelet complexes that promote inflammation in thrombosis and restenosis.

Amino Acid Sequence↗
PubMed2005

Staged initial percutaneous coronary intervention followed by valve surgery ("hybrid approach") for patients with complex coronary and valve disease.

OBJECTIVES: The goal of this study was to determine if a "hybrid" approach to the treatment of complex combined coronary and valve disease is superior to the results predicted by a Society of Thoracic Surgeons' (STS) algorithm with conventional coronary artery bypass graft (CABG)/valve surgery in high-risk patients. BACKGROUND: With advancements in percutaneous coronary interventions (PCIs), some patients requiring coronary revascularization and valve surgery may benefit from a hybrid approach involving initial planned PCI followed by valve surgery, rather than conventional CABG/valve surgery. METHODS: We retrospectively analyzed 26 consecutive patients with coronary artery and valve disease who underwent planned initial PCI followed by valve surgery during the same hospital stay between September 1997 and August 2003. We calculated the predicted mortality at the time of PCI and compared it with the observed mortality. RESULTS: There were 12 male and 14 female patients with a median age of 72 years (range 53 to 91 years). Balloon angioplasty was performed in all patients, followed by stenting in 22 (85%) patients. Within a median of 5 days (range 0 to 14 days), 15 patients (58%) underwent primary and 11 patients (42%) underwent re-operative valve surgery. Operative mortality was 1 of 26 patients (3.8%), dramatically lower than the STS-predicted mortality of 22%. Median blood loss was 900 ml, and 22 patients (85%) required blood transfusions. Survival at 1, 3, and 5 years was 78%, 56%, and 44%, respectively. CONCLUSIONS: Hybrid initial PCI followed by staged valve surgery represents an excellent alternative to conventional CABG/valve surgery in some high-risk patients, particularly those who present in shock after myocardial infarction. Lower mortality rates come at the cost of more bleeding and transfusion requirements.

Aged↗
PubMed2005

Inflammation as a mechanism and therapeutic target for in-stent restenosis.

Restenosis following coronary stenting has long been attributed to neointimal proliferation, thrombosis, and negative remodeling. More recently, the important role of inflammation in vascular healing has also been increasingly well understood. From animal models and from clinical experience, we know that endothelial injury, platelet and leukocyte interactions, and subcellular chemoattractant and inflammatory mediators are pivotal in the development of the inflammatory response following stent implantation. By examining the specific mechanisms governing the inflammatory response to percutaneous coronary intervention, we may gain insight into potential therapeutic targets and strategies to prevent restenosis in clinical practice.

Angioplasty, Balloon, Coronary↗
PubMed2004

Comparison of the risk of vascular complications associated with femoral and radial access coronary catheterization procedures in obese versus nonobese patients.

In this retrospective review of 5,234 cardiac catheterizations and percutaneous coronary interventions, the rate of vascular complications was highest in extremely thin and morbidly obese patients and lowest in moderately obese patients, consistent with the previously reported "obesity paradox." The use of transradial access and arterial access closure devices was associated with reduced vascular complications in the population of obese patients.

Aged↗
PubMed2004

Transcription factor CHF1/Hey2 regulates neointimal formation in vivo and vascular smooth muscle proliferation and migration in vitro.

OBJECTIVE: To determine the role of the cardiovascular-restricted, hairy-related bHLH transcription factor, CHF1/Hey2, in the biological response to vascular injury. METHODS AND RESULTS: We investigated the response of CHF1/Hey2-deficient mice to vascular injury in vivo and the response of primary cultured vascular smooth muscle cells (VSMCs) from these mice to growth factors in vitro. Neointima formation after arterial wire injury is decreased in knockout (KO) compared with wild-type (WT) mice (0.025+/-0.011 mm2 in WT [n=13]) versus 0.016+/-0.008 mm2 in KO (n=12; P<0.05) and is accompanied by reduced cellular proliferation. CHF1/Hey2-deficient VSMCs proliferate slowly compared with WT VSMCs and also show decreased migration in response to platelet-derived growth factor (PDGF) (62.6+/-10.3 CPF versus 37.2+/-13.5 CPF; P<0.01) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) (27.4+/-7.7 CPF versus 6.4+/-3.7 CPF, P<0.05). Furthermore, lamellipodia formation and membrane ruffling induced by these chemoattractants are diminished in KO VSMCs, which is correlated with decreased activation of the small GTPase Rac1. Although total Rac1 protein was not changed in KO VSMCs, the level of the Rac guanine exchange factor (GEF), Sos1, was decreased. CONCLUSIONS: CHF1/Hey2 is an important regulator of vascular smooth muscle cell (VSMC) accumulation during vascular remodeling and responsiveness to growth factors in vitro.

Animals↗
PubMed2004

Decreased neointimal formation in Nox2-deficient mice reveals a direct role for NADPH oxidase in the response to arterial injury.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced, in part, from NADPH oxidase in response to host invasion and tissue injury. Defects in NADPH oxidase impair host defense; however, the role of ROS and RNS in the response to tissue injury is not known. We addressed this issue by subjecting leukocyte oxidase (Nox2)-deficient (Nox2-/-) mice to arterial injury. Femoral artery injury was associated with increased Nox2 expression, ROS/RNS production, and oxidative protein and lipid modification in wild-type mice. In Nox2-/- mice, RNS-mediated protein oxidation, as monitored by protein nitrotyrosine content, was significantly diminished. This was accompanied by reduced neointimal proliferation, as monitored by intimal thickness and intimal/medial ratio, in Nox2-/- compared to wild-type mice. In addition, Nox2 deficiency led to reduced cellular proliferation and leukocyte accumulation. These data indicate that Nox2-mediated oxidant production has a requisite role in the response to tissue injury.

Animals↗
PubMed2004

Macrophage migration inhibitory factor deficiency impairs atherosclerosis in low-density lipoprotein receptor-deficient mice.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine expressed widely by vascular cells. However, scant in vivo evidence supports direct participation of MIF in atherogenesis. Therefore, we investigated whether deficiency of MIF modulates atherosclerotic lesion formation and composition in low-density lipoprotein receptor-deficient (LDLr-/-) mice. METHODS AND RESULTS: MIF-/-LDLr-/- and LDLr-/- mice were generated and consumed an atherogenic diet for 12 or 26 weeks. MIF-/-LDLr-/- mice had significantly reduced abdominal aorta lipid deposition and intimal thickening from aortic arch throughout the abdominal aorta compared with LDLr-/- mice. Marked retardation of atherosclerosis over time in MIF-deficient mice accompanied decreased lesion cell proliferation. At 26 weeks, 20% of MIF-deficient mice developed only early, fatty streak-like lesions, whereas >80% of LDLr-/- mice developed advanced lesions containing calcification and lipid cores. Analysis of smooth muscle cells from mouse aortae demonstrated that MIF deficiency reduced smooth muscle cell proliferation, cysteine protease expression, and elastinolytic and collagenolytic activities. CONCLUSIONS: Deficiency of MIF reduces atherogenesis in LDLr-/- mice. These results provide novel insight into inflammatory pathways operating in atheromata and identify a new potential target for modulating atherogenesis.

Animals↗
PubMed2004

KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation.

The vascular endothelium is a critical regulator of vascular function. Diverse stimuli such as proinflammatory cytokines and hemodynamic forces modulate endothelial phenotype and thereby impact on the development of vascular disease states. Therefore, identification of the regulatory factors that mediate the effects of these stimuli on endothelial function is of considerable interest. Transcriptional profiling studies identified the Kruppel-like factor (KLF)2 as being inhibited by the inflammatory cytokine interleukin-1beta and induced by laminar shear stress in cultured human umbilical vein endothelial cells. Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. In addition, KLF2 overexpression potently inhibited the induction of vascular cell adhesion molecule-1 and endothelial adhesion molecule E-selectin in response to various proinflammatory cytokines. Consistent with these observations, in vitro flow assays demonstrate that T cell attachment and rolling are markedly attenuated in endothelial monolayers transduced with KLF2. Finally, our studies implicate recruitment by KLF2 of the transcriptional coactivator cyclic AMP response element-binding protein (CBP/p300) as a unifying mechanism for these various effects. These data implicate KLF2 as a novel regulator of endothelial activation in response to proinflammatory stimuli.

Base Sequence↗
PubMed2004

Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation.

Transforming growth factor (TGF)-beta(1) is a pleiotropic growth factor with known inhibitory effects on immune cell activation. However, the specific mechanism(s) and in vivo significance of the effectors of TGF-beta(1) modulation in the context of vascular inflammation are not well characterized. The chemokine monocyte chemoattractant protein (MCP)-1 is critical for the recruitment of macrophages in inflammatory disease states. In this study, we provide definitive evidence that the ability of TGF-beta(1) to inhibit MCP-1 expression is mediated via its effector Smad3. Adenoviral overexpression of Smad3 potently repressed inducible expression of endogenous MCP-1. Conversely, TGF-beta(1) inhibition of cytokine-mediated induction of MCP-1 expression was completely blocked in Smad3-deficient macrophages. Consistent with this impaired response, cardiac allografts in Smad3-deficient mice developed accelerated intimal hyperplasia with increased infiltration of adventitial macrophages expressing MCP-1. Previous studies show that MCP-1 inducibility is regulated by an AP-1 complex composed of c-Jun/c-Fos heterodimers. We demonstrate that the inhibitory effect of Smad3 occurs via a novel antagonistic effect of Smad3 on AP-1 DNA-protein binding and activity. Thus, Smad3 plays an essential role in modulating vascular inflammation characteristic of transplant-associated arteriopathy, is important in regulating MCP-1 expression, and plays a critical role in the ability of TGF-beta(1) to repress stimuli from a major inflammatory signaling pathway.

Animals↗
PubMed2004

GP IIb/IIIa inhibition with eptifibatide lowers levels of soluble CD40L and RANTES after percutaneous coronary intervention.

Platelets are the most abundant blood source of CD40L, a proinflammatory and prothrombotic costimulatory molecule implicated in atherosclerosis. Agonist stimulation results in the secretion of a soluble form of CD40L (sCD40L) and GP IIb/IIIa receptor inhibition blocks secretion of sCD40L in vitro. However, the effect of GP IIb/IIIa inhibition on sCD40L levels in humans is unknown. Plasma sCD40L and inflammatory markers were measured (t = 0, 0.5, 2, and 24 hr post-PCI) in a cohort of patients receiving abciximab (n = 15), eptifibatide (n = 15), or no GP IIb/IIIa inhibitor (n = 15). PCI in the absence of GP IIb/IIIa inhibitor was associated with a small but measurable rise in sCD40L and the platelet-derived chemokine RANTES. In contrast, eptifibatide significantly lowered baseline sCD40L (P = 0.018) and RANTES (P = 0.006) levels. This effect was not observed with abciximab. GP IIb/IIIa inhibition with eptifibatide lowers levels of sCD40L and RANTES post-stenting, possibly conferring anti-inflammatory as well as antithrombotic effects.

Abciximab↗