Bio

Clinical Focus


  • Cardiovascular Disease
  • Marfan Syndrome and Aortic Disorders
  • Aortic Disease

Academic Appointments


Professional Education


  • Fellowship:Stanford University School of Medicine (2003) CA
  • Internship:Stanford University School of Medicine (1998) CA
  • Residency:Stanford University School of Medicine (2000) CA
  • Board Certification: Cardiovascular Disease, American Board of Internal Medicine (2003)
  • Medical Education:Boston University School of Medicine (1997) MA
  • BA, Cornell University, Biophysics (1989)
  • MD, PhD, Boston University Med School, Biophysics (1997)

Research & Scholarship

Current Research and Scholarly Interests


Dr. Spin is pursuing fundamental issues relating to smooth muscle cell (SMC) biology. SMCs play crucial roles in vascular development, homeostasis, and disease. He has examined gene expression within the vascular wall, identifying patterns and pathways that characterized atherogenesis. He has also studied the biology of differentiation and phenotypic switching in vascular SMCs, first identifying differentially regulated genes associated with SMC lineage determination, and then focusing on the epigenetic regulation of SMC differentiation state. Most recently he has examined the role of microRNAs in the regulation of SMC phenotype, and studied the biology of aortic aneurysm development in mouse models.

Publications

Journal Articles


  • Hemodynamic regulation of reactive oxygen species: implications for vascular diseases. Antioxidants & redox signaling Raaz, U., Toh, R., Maegdefessel, L., Adam, M., Nakagami, F., Emrich, F. C., Spin, J. M., Tsao, P. S. 2014; 20 (6): 914-928

    Abstract

    Significance: Arterial blood vessels functionally and structurally adapt to altering hemodynamic forces in order to accommodate changing needs and to provide stress homeostasis. This ability is achieved at the cellular level by converting mechanical stimulation into biochemical signals (i.e., mechanotransduction). Whereas physiological mechanical stress helps to maintain vascular structure and function, pathologic or aberrant stress may impair cellular mechano-signaling, and initiate or augment cellular processes which drive disease. Recent advances: Reactive oxygen species (ROS) may represent an intriguing class of mechanically- regulated second messengers. Chronically enhanced ROS-generation may be induced by adverse mechanical stresses, and is associated with a multitude of vascular diseases. Although a causal relationship has clearly been demonstrated in large numbers of animal studies, an effective ROS-modulating therapy still remains to be established by clinical studies. Critical issues and Future directions: This review article focuses on the role of various mechanical forces (in the form of laminar shear stress, oscillatory shear stress or cyclic stretch) as modulators of ROS- driven signaling, and their subsequent effects on vascular biology and homeostasis, as well as on specific diseases such as arteriosclerosis, hypertension and abdominal aortic aneurysms. Specifically, it highlights the significance of the various NADPH oxidase (NOX) isoforms as critical ROS generators in the vasculature. Directed targeting of defined components in the complex network of ROS (mechano)signaling may represent a key for successful translation of experimental findings into clinical practice.

    View details for DOI 10.1089/ars.2013.5507

    View details for PubMedID 23879326

  • Micromanaging Abdominal Aortic Aneurysms INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Maegdefessel, L., Spin, J. M., Adam, M., Raaz, U., Toh, R., Nakagami, F., Tsao, P. S. 2013; 14 (7): 14374-14394

    Abstract

    The contribution of abdominal aortic aneurysm (AAA) disease to human morbidity and mortality has increased in the aging, industrialized world. In response, extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of the diseased aorta. This work aims to develop novel diagnostic and therapeutic strategies to limit AAA expansion and, ultimately, rupture. Contributions from multiple research groups have uncovered a complex transcriptional and post-transcriptional regulatory milieu, which is believed to be essential for maintaining aortic vascular homeostasis. Recently, novel small noncoding RNAs, called microRNAs, have been identified as important transcriptional and post-transcriptional inhibitors of gene expression. MicroRNAs are thought to "fine tune" the translational output of their target messenger RNAs (mRNAs) by promoting mRNA degradation or inhibiting translation. With the discovery that microRNAs act as powerful regulators in the context of a wide variety of diseases, it is only logical that microRNAs be thoroughly explored as potential therapeutic entities. This current review summarizes interesting findings regarding the intriguing roles and benefits of microRNA expression modulation during AAA initiation and propagation. These studies utilize disease-relevant murine models, as well as human tissue from patients undergoing surgical aortic aneurysm repair. Furthermore, we critically examine future therapeutic strategies with regard to their clinical and translational feasibility.

    View details for DOI 10.3390/ijms140714374

    View details for Web of Science ID 000322171700085

    View details for PubMedID 23852016

  • MicroRNAs in Abdominal Aortic Aneurysm. Current vascular pharmacology Adam, M., Raaz, U., Spin, J. M., Tsao, P. S. 2013

    Abstract

    Abdominal aortic aneurysms (AAA) are an important source of morbidity and mortality in the U.S. and worldwide. Treatment options are limited, with open surgery or endovascular repair remaining the only curative treatments. Classical cardiovascular medications have generally failed to prevent or significantly alter AAA formation or progression. Therefore, there is a tremendous need for better therapeutic approaches. With increasing knowledge of microRNA (miR) regulation in the context of cardiovascular disease, and with improving technical options permitting alteration of miR-expression levels in vitro and in vivo, we are offered a glimpse into the diagnostic and therapeutic possibilities of using miRs to treat vascular pathobiology. This review focuses on the role of miRs in aneurysmal disease of the abdominal aorta, summarizing recent publications regarding this topic, and outlining known effects of relevant miRs in AAA formation, including miR-21 and miR-29b. Despite there being only limited studies available, several other miRs also display clear potential for alteration of the disease process including miR-26a, the miR-17-92-cluster, miRs-221/222, miR-133 and miR-146a. While studies have shown that miRs can regulate the activity and interplay of vascular inflammatory cells, endothelial cells, smooth muscle cells and fibroblasts, all key elements leading to AAA formation, much work remains to be done.

    View details for PubMedID 23713862

  • Loss of CDKN2B Promotes p53-Dependent Smooth Muscle Cell Apoptosis and Aneurysm Formation ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Leeper, N. J., Raiesdana, A., Kojima, Y., Kundu, R. K., Cheng, H., Maegdefessel, L., Toh, R., Ahn, G., Ali, Z. A., Anderson, D. R., Miller, C. L., Roberts, S. C., Spin, J. M., de Almeida, P. E., Wu, J. C., Xu, B., Cheng, K., Quertermous, M., Kundu, S., Kortekaas, K. E., Berzin, E., Downing, K. P., Dalman, R. L., Tsao, P. S., Schadt, E. E., Owens, G. K., Quertermous, T. 2013; 33 (1): E1-?

    Abstract

    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 Web of Science ID 000312392500001

    View details for PubMedID 23162013

  • Vascular smooth muscle cell phenotypic plasticity: focus on chromatin remodelling CARDIOVASCULAR RESEARCH Spin, J. M., Maegdefessel, L., Tsao, P. S. 2012; 95 (2): 147-155

    Abstract

    Differentiated vascular smooth muscle cells (SMCs) retain the capacity to modify their phenotype in response to inflammation or injury. This phenotypic switching is a crucial component of vascular disease, and is partly dependent on epigenetic regulation. An appreciation has been building in the literature for the essential role chromatin remodelling plays both in SMC lineage determination and in influencing changes in SMC behaviour and state. This process includes numerous chromatin regulatory elements and pathways such as histone acetyltransferases, deacetylases, and methyltransferases and other factors that act at SMC-specific marker sites to silence or permit access to the cellular transcriptional machinery and on other key regulatory elements such as myocardin and Kruppel-like factor 4 (KLF4). Various stimuli known to alter the SMC phenotype, such as transforming growth factor beta (TGF-?), platelet-derived growth factor (PDGF), oxidized phospholipids, and retinoic acid, appear to act in part through effects upon SMC chromatin structure. In recent years, specific covalent histone modifications that appear to establish SMC determinacy have been identified, while others alter the differentiation state. In this article, we review the mechanisms of chromatin remodelling as it applies to the SMC phenotype.

    View details for DOI 10.1093/cvr/cvs098

    View details for Web of Science ID 000306141100004

    View details for PubMedID 22362814

  • MicroRNA-21 Blocks Abdominal Aortic Aneurysm Development and Nicotine-Augmented Expansion SCIENCE TRANSLATIONAL MEDICINE Maegdefessel, L., Azuma, J., Toh, R., Deng, A., Merk, D. R., Raiesdana, A., Leeper, N. J., Raaz, U., Schoelmerich, A. M., McConnell, M. V., Dalman, R. L., Spin, J. M., Tsao, P. S. 2012; 4 (122)

    Abstract

    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 Maegdefessel, L., Azuma, J., Toh, R., Merk, D. R., Deng, A., Chin, J. T., Raaz, U., Schoelmerich, A. M., Raiesdana, A., Leeper, N. J., McConnell, M. V., Dalman, R. L., Spin, J. M., Tsao, P. S. 2012; 122 (2): 497-506

    Abstract

    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

  • miR-29b Participates in Early Aneurysm Development in Marfan Syndrome CIRCULATION RESEARCH Merk, D. R., Chin, J. T., Dake, B. A., Maegdefessel, L., Miller, M. O., Kimura, N., Tsao, P. S., Iosef, C., Berry, G. J., Mohr, F. W., Spin, J. M., Alvira, C. M., Robbins, R. C., Fischbein, M. P. 2012; 110 (2): 312-?

    Abstract

    Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-? (TGF-?) signaling. Although TGF-? blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-? causes aneurysms remain ill-defined.We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS.Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1(C1039G/+)) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/+) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/+) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor ?B, a repressor of miR-29b, and a factor suppressed by TGF-?, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor ?B inhibitor increased miR-29b levels, whereas TGF-? blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/+) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies.We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.

    View details for DOI 10.1161/CIRCRESAHA.111.253740

    View details for Web of Science ID 000299432600015

    View details for PubMedID 22116819

  • In Vivo Functional and Transcriptional Profiling of Bone Marrow Stem Cells After Transplantation Into Ischemic Myocardium ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Sheikh, A. Y., Huber, B. C., Narsinh, K. H., Spin, J. M., van der Bogt, K., de Almeida, P. E., Ransohoff, K. J., Kraft, D. L., Fajardo, G., Ardigo, D., Ransohoff, J., Bernstein, D., Fischbein, M. P., Robbins, R. C., Wu, J. C. 2012; 32 (1): 92-102

    Abstract

    Clinical trials of bone marrow-derived stem cell therapy for the heart have yielded variable results. The basic mechanism(s) that underlies their potential efficacy remains unknown. In the present study, we evaluated the survival kinetics, transcriptional response, and functional outcome of intramyocardial bone marrow mononuclear cell (BMMC) transplantation for cardiac repair in a murine myocardial infarction model.We used bioluminescence imaging and high-throughput transcriptional profiling to evaluate the in vivo survival kinetics and gene expression changes of transplanted BMMCs after their engraftment into ischemic myocardium. Our results demonstrate short-lived survival of cells following transplant, with less than 1% of cells surviving by 6 weeks posttransplantation. Moreover, transcriptomic analysis of BMMCs revealed nonspecific upregulation of various cell regulatory genes, with a marked downregulation of cell differentiation and maturation pathways. BMMC therapy caused limited improvement of heart function as assessed by echocardiography, invasive hemodynamics, and positron emission tomography. Histological evaluation of cell fate further confirmed findings of the in vivo cell tracking and transcriptomic analysis.Collectively, these data suggest that BMMC therapy, in its present iteration, may be less efficacious than once thought. Additional refinement of existing cell delivery protocols should be considered to induce better therapeutic efficacy.

    View details for DOI 10.1161/ATVBAHA.111.238618

    View details for Web of Science ID 000298288700014

    View details for PubMedID 22034515

  • Cardiac pressure overload hypertrophy is differentially regulated by beta-adrenergic receptor subtypes AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Zhao, M., Fajardo, G., Urashima, T., Spin, J. M., Poorfarahani, S., Rajagopalan, V., Diem Huynh, D., Connolly, A., Quertermous, T., Bernstein, D. 2011; 301 (4): H1461-H1470

    Abstract

    In isolated myocytes, hypertrophy induced by norepinephrine is mediated via ?(1)-adrenergic receptors (ARs) and not ?-ARs. However, mice with deletions of both major cardiac ?(1)-ARs still develop hypertrophy in response to pressure overload. Our purpose was to better define the role of ?-AR subtypes in regulating cardiac hypertrophy in vivo, important given the widespread clinical use of ?-AR antagonists and the likelihood that patients treated with these agents could develop conditions of further afterload stress. Mice with deletions of ?(1), ?(2), or both ?(1)- and ?(2)-ARs were subjected to transverse aortic constriction (TAC). After 3 wk, ?(1)(-/-) showed a 21% increase in heart to body weight vs. sham controls, similar to wild type, whereas ?(2)(-/-) developed exaggerated (49% increase) hypertrophy. Only when both ?-ARs were ablated (?(1)?(2)(-/-)) was hypertrophy totally abolished. Cardiac function was preserved in all genotypes. Several known inhibitors of cardiac hypertrophy (FK506 binding protein 5, thioredoxin interacting protein, and S100A9) were upregulated in ?(1)?(2)(-/-) compared with the other genotypes, whereas transforming growth factor-?(2), a positive mediator of hypertrophy was upregulated in all genotypes except the ?(1)?(2)(-/-). In contrast to recent reports suggesting that angiogenesis plays a critical role in regulating cardiac hypertrophy-induced heart failure, we found no evidence that angiogenesis or its regulators (VEGF, Hif1?, and p53) play a role in compensated cardiac hypertrophy. Pressure overload hypertrophy in vivo is dependent on a coordination of signaling through both ?(1)- and ?(2)-ARs, mediated through several key cardiac remodeling pathways. Angiogenesis is not a prerequisite for compensated cardiac hypertrophy.

    View details for DOI 10.1152/ajpheart.00453.2010

    View details for Web of Science ID 000295360100028

    View details for PubMedID 21705675

  • Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm PHYSIOLOGICAL GENOMICS Spin, J. M., Hsu, M., Azuma, J., Tedesco, M. M., Deng, A., Dyer, J. S., Maegdefessel, L., Dalman, R. L., Tsao, P. S. 2011; 43 (17): 993-1003

    Abstract

    We sought to characterize temporal gene expression changes in the murine angiotensin II (ANG II)-ApoE-/- model of abdominal aortic aneurysm (AAA). Aortic ultrasound measurements were obtained over the 28-day time-course. Harvested suprarenal aortic segments were evaluated with whole genome expression profiling at 7, 14, and 28 days using the Agilent Whole Mouse Genome microarray platform and Statistical Analysis of Microarrays at a false discovery rate of <1%. A group of angiotensin-treated mice experienced contained rupture (CR) within 7 days and were analyzed separately. Progressive aortic dilatation occurred throughout the treatment period. However, the numerous early expression differences between ANG II-treated and control were not sustained over time. Ontologic analysis revealed widespread upregulation of inflammatory, immune, and matrix remodeling genes with ANG II treatment, among other pathways such as apoptosis, cell cycling, angiogenesis, and p53 signaling. CR aneurysms displayed significant decreases in TGF-?/BMP-pathway signaling, MAPK signaling, and ErbB signaling genes vs. non-CR/ANG II-treated samples. We also performed literature-based network analysis, extracting numerous highly interconnected genes associated with aneurysm development such as Spp1, Myd88, Adam17 and Lox. 1) ANG II treatment induces extensive early differential expression changes involving abundant signaling pathways in the suprarenal abdominal aorta, particularly wide-ranging increases in inflammatory genes with aneurysm development. 2) These gene expression changes appear to dissipate with time despite continued growth, suggesting that early changes in gene expression influence disease progression in this AAA model, and that the aortic tissue adapts to prolonged ANG II infusion. 3) Network analysis identified nexus genes that may constitute aneurysm biomarkers or therapeutic targets.

    View details for DOI 10.1152/physiolgenomics.00044.2011

    View details for Web of Science ID 000294730000002

    View details for PubMedID 21712436

  • MicroRNA-26a Is a Novel Regulator of Vascular Smooth Muscle Cell Function JOURNAL OF CELLULAR PHYSIOLOGY Leeper, N. J., Raiesdana, A., Kojima, Y., Chun, H. J., Azuma, J., Maegdefessel, L., Kundu, R. K., Quertermous, T., Tsao, P. S., Spin, J. M. 2011; 226 (4): 1035-1043

    Abstract

    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?

    View details for DOI 10.1002/jcp.22422

    View details for Web of Science ID 000287258800019

    View details for PubMedID 20857419

  • Gene Mutations and Familial Thoracic Aortic Aneurysms A Walk on the Mild Side CIRCULATION-CARDIOVASCULAR GENETICS Spin, J. M. 2011; 4 (1): 4-6
  • Chromatin Remodeling Pathways in Smooth Muscle Cell Differentiation, and Evidence for an Integral Role for p300 PLOS ONE Spin, J. M., Quertermous, T., Tsao, P. S. 2010; 5 (12)

    Abstract

    Phenotypic alteration of vascular smooth muscle cells (SMC) in response to injury or inflammation is an essential component of vascular disease. Evidence suggests that this process is dependent on epigenetic regulatory processes. P300, a histone acetyltransferase (HAT), activates crucial muscle-specific promoters in terminal (non-SMC) myocyte differentiation, and may be essential to SMC modulation as well.We performed a subanalysis examining transcriptional time-course microarray data obtained using the A404 model of SMC differentiation. Numerous chromatin remodeling genes (up to 62% of such genes on our array platform) showed significant regulation during differentiation. Members of several chromatin-remodeling families demonstrated involvement, including factors instrumental in histone modification, chromatin assembly-disassembly and DNA silencing, suggesting complex, multi-level systemic epigenetic regulation. Further, trichostatin A, a histone deacetylase inhibitor, accelerated expression of SMC differentiation markers in this model. Ontology analysis indicated a high degree of p300 involvement in SMC differentiation, with 60.7% of the known p300 interactome showing significant expression changes. Knockdown of p300 expression accelerated SMC differentiation in A404 cells and human SMCs, while inhibition of p300 HAT activity blunted SMC differentiation. The results suggest a central but complex role for p300 in SMC phenotypic modulation.Our results support the hypothesis that chromatin remodeling is important for SMC phenotypic switching, and detail wide-ranging involvement of several epigenetic modification families. Additionally, the transcriptional coactivator p300 may be partially degraded during SMC differentiation, leaving an activated subpopulation with increased HAT activity and SMC differentiation-gene specificity.

    View details for DOI 10.1371/journal.pone.0014301

    View details for Web of Science ID 000285246900013

    View details for PubMedID 21179216

  • New options with dabigatran etexilate in anticoagulant therapy. Vascular health and risk management Maegdefessel, L., Spin, J. M., Azuma, J., Tsao, P. S. 2010; 6: 339-349

    Abstract

    Thrombosis, the localized clotting of blood, occurs in both the arterial and venous circulation, and has a major impact on health outcomes. The primary etiology of myocardial infarctions, and approximately 80% of strokes, is acute arterial thrombosis. In combination this represents the most common cause of death in the Western world, while the third leading cause of cardiovascular-associated death is venous thromboembolism. An understanding of the pathogenic changes in the vessel wall and the blood that result in thrombosis is crucial for developing safer and more effective antithrombotic drugs. Dabigatran etexilate belongs to a new class of direct thrombin inhibitors. Following oral administration, dabigatran reaches peak plasma concentrations within 2 hours, shows linear pharmacokinetics, and a limited (but important) amount of direct drug interactions. Given once daily at 150 mg or 220 mg, it has proven to be competitive with enoxaparin in the prevention of venous thromboembolism after major orthopedic surgery, with a comparable safety profile. For stroke prevention in patients suffering from atrial fibrillation, dabigatran administered at a dose of 110 mg twice daily was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of hemorrhage. Dabigatran given at a dose of 150 mg twice daily, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. Oral bioavailability of dabigatran, together with a rapid onset and offset of action and predictable anticoagulation response, makes this newly available antithrombotic drug an attractive alternative to traditional anticoagulant therapies for numerous thrombosis-related indications.

    View details for PubMedID 20531953

  • Analysis of In Situ and Ex Vivo Vascular Endothelial Growth Factor Receptor Expression During Experimental Aortic Aneurysm Progression ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Tedesco, M. M., Terashima, M., Blankenberg, F. G., Levashova, Z., Spin, J. M., Backer, M. V., Backer, J. M., Sho, M., Sho, E., McConnell, M. V., Dalman, R. L. 2009; 29 (10): 1452-?

    Abstract

    Mural inflammation and neovascularization are characteristic pathological features of abdominal aortic aneurysm (AAA) disease. Vascular endothelial growth factor receptor (VEGFR) expression may also mediate AAA growth and rupture. We examined VEGFR expression as a function of AAA disease progression in the Apolipoprotein E-deficient (Apo E(-/-)) murine AAA model.Apo E(-/-) mice maintained on a high-fat diet underwent continuous infusion with angiotensin II at 1000 ng/kg/min (Ang II) or vehicle (Control) via subcutaneous osmotic pump. Serial transabdominal ultrasound measurements of abdominal aortic diameter were recorded (n=16 mice, 3 to 4 time points per mouse) for up to 28 days. Near-infrared receptor fluorescent (NIRF) imaging was performed on Ang II mice (n=9) and Controls (n=5) with scVEGF/Cy, a single-chain VEGF homo-dimer labeled with Cy 5.5 fluorescent tracer (7 to 18 microg/mouse IV). NIRF with inactivated single chain VEGF/Cy tracer (scVEGF/In, 18 microg/mouse IV) was performed on 2 additional Ang II mice to control for nonreceptor-mediated tracer binding and uptake. After image acquisition and sacrifice, aortae were harvested for analysis. An additional AAA mouse cohort received either an oral angiogenesis inhibitor or suitable negative or positive controls to clarify the significance of angiogenesis in experimental aneurysm progression. Aneurysms developed in the suprarenal aortic segment of all Ang II mice. Significantly greater fluorescent signal was obtained from aneurysmal aorta as compared to remote, uninvolved aortic segments in Ang II scVEGF/Cy mice or AAA in scVEGF/In mice or suprarenal aortic segments in Control mice. Signal intensity increased in a diameter-dependent fashion in aneurysmal segments. Immunostaining confirmed mural VEGFR-2 expression in medial smooth muscle cells. Treatment with an angiogenesis inhibitor attenuated AAA formation while decreasing mural macrophage infiltration and CD-31(+) cell density.Mural VEGFR expression, as determined by scVEGF/Cy fluorescent imaging and VEGFR-2 immunostaining, increases in experimental AAAs in a diameter-dependent fashion. Angiogenesis inhibition limits AAA progression. Clinical VEGFR expression imaging strategies, if feasible, may improve real-time monitoring of AAA disease progression and response to suppressive strategies.

    View details for DOI 10.1161/ATVBAHA.109.187757

    View details for Web of Science ID 000269848600010

    View details for PubMedID 19574559

  • Frontiers in nephrology: Genomic approaches to understanding the molecular basis of atherosclerosis JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Ashley, E. A., Spin, J. M., Tabibiazar, R., Quertermous, T. 2007; 18 (11): 2853-2862

    Abstract

    Atherosclerosis is a complex multicellular disease that is responsible for pathology in various organ systems. The understanding of its initiation and progression has been enhanced in recent years by the application of high-throughput genomic tools such as the microarray. Increasing in genomic coverage, such tools allow a view of the disease unaffected by previous conjecture as to the primary signal of interest. New statistical tools and pathway modeling techniques have established definitively for the first time the central role of inflammation in this process. This article reviews the genomic literature relating to atherosclerosis from cell culture, animal models, and human tissues. In this comparison of these differing approaches, the available data are synthesized to reach a new understanding of the complex interplay between vascular wall and immune system components.

    View details for DOI 10.1681/ASN.2007040514

    View details for Web of Science ID 000250737600012

    View details for PubMedID 17942952

  • Network analysis of human in-stent restenosis CIRCULATION Ashley, E. A., Ferrara, R., King, J. Y., Vailaya, A., Kuchinsky, A., He, X., Byers, B., Gerckens, U., Oblin, S., Tsalenko, A., Soito, A., Spin, J. M., Tabibiazar, R., Connolly, A. J., Simpson, J. B., Grube, E., Quertermous, T. 2006; 114 (24): 2644-2654

    Abstract

    Recent successes in the treatment of in-stent restenosis (ISR) by drug-eluting stents belie the challenges still faced in certain lesions and patient groups. We analyzed human coronary atheroma in de novo and restenotic disease to identify targets of therapy that might avoid these limitations.We recruited 89 patients who underwent coronary atherectomy for de novo atherosclerosis (n=55) or in-stent restenosis (ISR) of a bare metal stent (n=34). Samples were fixed for histology, and gene expression was assessed with a dual-dye 22,000 oligonucleotide microarray. Histological analysis revealed significantly greater cellularity and significantly fewer inflammatory infiltrates and lipid pools in the ISR group. Gene ontology analysis demonstrated the prominence of cell proliferation programs in ISR and inflammation/immune programs in de novo restenosis. Network analysis, which combines semantic mining of the published literature with the expression signature of ISR, revealed gene expression modules suggested as candidates for selective inhibition of restenotic disease. Two modules are presented in more detail, the procollagen type 1 alpha2 gene and the ADAM17/tumor necrosis factor-alpha converting enzyme gene. We tested our contention that this method is capable of identifying successful targets of therapy by comparing mean significance scores for networks generated from subsets of the published literature containing the terms "sirolimus" or "paclitaxel." In addition, we generated 2 large networks with sirolimus and paclitaxel at their centers. Both analyses revealed higher mean values for sirolimus, suggesting that this agent has a broader suppressive action against ISR than paclitaxel.Comprehensive histological and gene network analysis of human ISR reveals potential targets for directed abrogation of restenotic disease and recapitulates the results of clinical trials of existing agents.

    View details for DOI 10.1161/CIRCULATIONAHA.106.637025

    View details for Web of Science ID 000243477800015

    View details for PubMedID 17145989

  • Molecular signatures determining coronary artery and saphenous vein smooth muscle cell phenotypes - Distinct responses to stimuli ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Deng, D. X., Spin, J. M., Tsalenko, A., Vailaya, A., Ben-Dor, A., Yakhini, Z., Tsao, P., Bruhn, L., Quertermous, T. 2006; 26 (5): 1058-1065

    Abstract

    Phenotypic differences between vascular smooth muscle cell (VSMC) subtypes lead to diverse pathological processes including atherosclerosis, postangioplasty restenosis and vein graft disease. To better understand the molecular mechanisms underlying functional differences among distinct SMC subtypes, we compared gene expression profiles and functional responses to oxidized low-density lipoprotein (OxLDL) and platelet-derived growth factor (PDGF) between cultured SMCs from human coronary artery (CASM) and saphenous vein (SVSM).OxLDL and PDGF elicited markedly different functional responses and expression profiles between the 2 SMC subtypes. In CASM, OxLDL inhibited cell proliferation and migration and modified gene expression of chemokines (CXCL10, CXCL11 and CXCL12), proinflammatory cytokines (IL-1, IL-6, and IL-18), insulin-like growth factor binding proteins (IGFBPs), and both endothelial and smooth muscle marker genes. In SVSM, OxLDL promoted proliferation partially via IGF1 signaling, activated NF-kappaB and phosphatidylinositol signaling pathways, and upregulated prostaglandin (PG) receptors and synthases. In untreated cells, alpha-chemokines, proinflammatory cytokines, and genes associated with apoptosis, inflammation, and lipid biosynthesis were higher in CASM, whereas some beta-chemokines, metalloproteinase inhibitors, and IGFBPs were higher in SVSM. Interestingly, the basal expression levels of these genes seemed closely related to their responses to OxLDL and PDGF. In summary, our results suggest dramatic differences in gene expression patterns and functional responses to OxLDL and PDGF between venous and arterial SMCs, with venous SMCs having stronger proliferative/migratory responses to stimuli but also higher expression of atheroprotective genes at baseline.These results reveal molecular signatures that define the distinct phenotypes characteristics of coronary artery and saphenous vein SMC subtypes.

    View details for DOI 10.1161/01.ATV.0000208185.16371.97

    View details for Web of Science ID 000236942400017

    View details for PubMedID 16456091

  • Transcriptional profiling of reporter genes used for molecular imaging of embryonic stem cell transplantation PHYSIOLOGICAL GENOMICS Wu, J. C., Spin, J. M., Cao, F., Lin, S. A., Xie, X. Y., Gheysens, O., Chen, I. Y., Sheikh, A. Y., Robbins, R. C., Tsalenko, A., Gambhir, S. S., Quertermous, T. 2006; 25 (1): 29-38

    Abstract

    Stem cell therapy offers exciting promise for treatment of ischemic heart disease. Recent advances in molecular imaging techniques now allow investigators to monitor cell fate noninvasively and repetitively. Here we examine the effects of a triple-fusion reporter gene on embryonic stem (ES) cell transcriptional profiles. Murine ES cells were stably transfected with a self-inactivating lentiviral vector carrying a triple-fusion (TF) construct consisting of fluorescence, bioluminescence, and positron emission tomography (PET) reporter genes. Fluorescence-activated cell sorting (FACS) analysis allowed isolation of stably transfected populations. Microarray studies comparing gene expression in nontransduced control ES cells vs. stably transduced ES cells expressing triple fusion (ES-TF) revealed some increases in transcriptional variability. Annotation analysis showed that ES-TF cells downregulated cell cycling, cell death, and protein and nucleic acid metabolism genes while upregulating homeostatic and anti-apoptosis genes. Despite these transcriptional changes, expression of the TF reporter gene had no significant effects on ES cell viability, proliferation, and differentiation capability. Importantly, transplantation studies in murine myocardium demonstrated the feasibility of tracking ES-TF cells in living subjects using bioluminescence and PET imaging. Taken together, this is the first study to analyze in detail the effects of reporter genes on molecular imaging of ES cells.

    View details for DOI 10.1152/physiolgenomics.00254.2005

    View details for Web of Science ID 000236722700004

    View details for PubMedID 16390873

  • Pathway analysis of coronary atherosclerosis PHYSIOLOGICAL GENOMICS King, J. Y., Ferrara, R., Tabibiazar, R., Spin, J. M., Chen, M. M., Kuchinsky, A., Vailaya, A., Kincaid, R., Tsalenko, A., Deng, D. X., Connolly, A., Zhang, P., Yang, E., Watt, C., Yakhini, Z., Ben-Dor, A., Adler, A., Bruhn, L., Tsao, P., Quertermous, T., Ashley, E. A. 2005; 23 (1): 103-118

    Abstract

    Large-scale gene expression studies provide significant insight into genes differentially regulated in disease processes such as cancer. However, these investigations offer limited understanding of multisystem, multicellular diseases such as atherosclerosis. A systems biology approach that accounts for gene interactions, incorporates nontranscriptionally regulated genes, and integrates prior knowledge offers many advantages. We performed a comprehensive gene level assessment of coronary atherosclerosis using 51 coronary artery segments isolated from the explanted hearts of 22 cardiac transplant patients. After histological grading of vascular segments according to American Heart Association guidelines, isolated RNA was hybridized onto a customized 22-K oligonucleotide microarray, and significance analysis of microarrays and gene ontology analyses were performed to identify significant gene expression profiles. Our studies revealed that loss of differentiated smooth muscle cell gene expression is the primary expression signature of disease progression in atherosclerosis. Furthermore, we provide insight into the severe form of coronary artery disease associated with diabetes, reporting an overabundance of immune and inflammatory signals in diabetics. We present a novel approach to pathway development based on connectivity, determined by language parsing of the published literature, and ranking, determined by the significance of differentially regulated genes in the network. In doing this, we identify highly connected "nexus" genes that are attractive candidates for therapeutic targeting and followup studies. Our use of pathway techniques to study atherosclerosis as an integrated network of gene interactions expands on traditional microarray analysis methods and emphasizes the significant advantages of a systems-based approach to analyzing complex disease.

    View details for DOI 10.1152/physiolgenomics.00101.2005

    View details for Web of Science ID 000232065200012

    View details for PubMedID 15942018

  • Signature patterns of gene expression in mouse atherosclerosis and their correlation to human coronary disease PHYSIOLOGICAL GENOMICS Tabibiazar, R., Wagner, R. A., Ashley, E. A., King, J. Y., Ferrara, R., Spin, J. M., Sanan, D. A., Narasimhan, B., Tibshirani, R., Tsao, P. S., Efron, B., Quertermous, T. 2005; 22 (2): 213-226

    Abstract

    The propensity for developing atherosclerosis is dependent on underlying genetic risk and varies as a function of age and exposure to environmental risk factors. Employing three mouse models with different disease susceptibility, two diets, and a longitudinal experimental design, it was possible to manipulate each of these factors to focus analysis on genes most likely to have a specific disease-related function. To identify differences in longitudinal gene expression patterns of atherosclerosis, we have developed and employed a statistical algorithm that relies on generalized regression and permutation analysis. Comprehensive annotation of the array with ontology and pathway terms has allowed rigorous identification of molecular and biological processes that underlie disease pathophysiology. The repertoire of atherosclerosis-related immunomodulatory genes has been extended, and additional fundamental pathways have been identified. This highly disease-specific group of mouse genes was combined with an extensive human coronary artery data set to identify a shared group of genes differentially regulated among atherosclerotic tissues from different species and different vascular beds. A small core subset of these differentially regulated genes was sufficient to accurately classify various stages of the disease in mouse. The same gene subset was also found to accurately classify human coronary lesion severity. In addition, this classifier gene set was able to distinguish with high accuracy atherectomy specimens from native coronary artery disease vs. those collected from in-stent restenosis lesions, thus identifying molecular differences between these two processes. These studies significantly focus efforts aimed at identifying central gene regulatory pathways that mediate atherosclerotic disease, and the identification of classification gene sets offers unique insights into potential diagnostic and therapeutic strategies in atherosclerotic disease.

    View details for DOI 10.1152/physiolgenomics.00001.2005

    View details for Web of Science ID 000230987900011

    View details for PubMedID 15870398

  • Mouse strain-specific differences in vascular wall gene expression and their relationship to vascular disease ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Tabibiazar, R., Wagner, R. A., Spin, J. M., Ashley, E. A., Narasimhan, B., Rubin, E. M., Efron, B., Tsao, P. S., Tibshirani, R., Quertermous, T. 2005; 25 (2): 302-308

    Abstract

    Different strains of inbred mice exhibit different susceptibility to the development of atherosclerosis. The C3H/HeJ and C57Bl/6 mice have been used in several studies aimed at understanding the genetic basis of atherosclerosis. Under controlled environmental conditions, variations in susceptibility to atherosclerosis reflect differences in genetic makeup, and these differences must be reflected in gene expression patterns that are temporally related to the development of disease. In this study, we sought to identify the genetic pathways that are differentially activated in the aortas of these mice.We performed genome-wide transcriptional profiling of aortas from C3H/HeJ and C57Bl/6 mice. Differences in gene expression were identified at baseline as well as during normal aging and longitudinal exposure to high-fat diet. The significance of these genes to the development of atherosclerosis was evaluated by observing their temporal pattern of expression in the well-studied apolipoprotein E model of atherosclerosis.Gene expression differences between the 2 strains suggest that aortas of C57Bl/6 mice have a higher genetic propensity to develop inflammation in response to appropriate atherogenic stimuli. This study expands the repertoire of factors in known disease-related signaling pathways and identifies novel candidate genes for future study. To gain insights into the molecular pathways that are differentially activated in strains of mice with varied susceptibility to atherosclerosis, we performed comprehensive transcriptional profiling of their vascular wall. Genes identified through these studies expand the repertoire of factors in disease-related signaling pathways and identify novel candidate genes in atherosclerosis.

    View details for DOI 10.1161/011.ATV.0000151372.86863.a5

    View details for Web of Science ID 000226594000009

    View details for PubMedID 15550693

  • Transcriptional profiling of in vitro smooth muscle cell differentiation identifies specific patterns of gene and pathway activation PHYSIOLOGICAL GENOMICS Spin, J. M., Nallamshetty, S., Tabibiazar, R., Ashley, E. A., King, J. Y., Chen, M., Tsao, P. S., Quertermous, T. 2004; 19 (3): 292-302

    Abstract

    Mesodermal and epidermal precursor cells undergo phenotypic changes during differentiation to the smooth muscle cell (SMC) lineage that are relevant to pathophysiological processes in the adult. Molecular mechanisms that underlie lineage determination and terminal differentiation of this cell type have received much attention, but the genetic program that regulates these processes has not been fully defined. Study of SMC differentiation has been facilitated by development of the P19-derived A404 embryonal cell line, which differentiates toward this lineage in the presence of retinoic acid and allows selection for cells adopting a SMC fate through a differentiation-specific drug marker. We sought to define global alterations in gene expression by studying A404 cells during SMC differentiation with oligonucleotide microarray transcriptional profiling. Using an in situ 60-mer array platform with more than 20,000 mouse genes derived from the National Institute on Aging clone set, we identified 2,739 genes that were significantly upregulated after differentiation was completed (false-detection ratio <1). These genes encode numerous markers known to characterize differentiated SMC, as well as many unknown factors. We further characterized the sequential patterns of gene expression during the differentiation time course, particularly for known transcription factor families, providing new insights into the regulation of the differentiation process. Changes in genes associated with specific biological ontology-based pathways were evaluated, and temporal trends were identified for functional pathways. In addition to confirming the utility of the A404 model, our data provide a large-scale perspective of gene regulation during SMC differentiation.

    View details for DOI 10.1152/physiolgenomics.00148.2004

    View details for Web of Science ID 000225840800007

    View details for PubMedID 15340120

  • Endothelial lipase modulates susceptibility to atherosclerosis in apolipoprotein-E-deficient mice JOURNAL OF BIOLOGICAL CHEMISTRY Ishida, T., Choi, S. S., Kundu, R. K., Spin, J., Yamashita, T., Hirata, K., Kojima, Y., Yokoyama, M., Cooper, A. D., Quertermous, T. 2004; 279 (43): 45085-45092

    Abstract

    Endothelial lipase (EL) expression correlates inversely with circulating high density lipoprotein (HDL) cholesterol levels in genetic mouse models, and human genetic variation in this locus has been linked to differences in HDL cholesterol levels. These data suggest a role for EL in the development of atherosclerotic vascular disease. To investigate this possibility, LIPG-null alleles were bred onto the apoE knockout background, and the homozygous double knockout animals were characterized. Both apoE knockout and double knockout mice had low HDL cholesterol levels when compared with wild-type mice, but the HDL cholesterol levels of the double knockout mice were higher than those of apoE knockout mice. Atherogenic very low density lipoprotein and intermediate density lipoprotein/low density lipoprotein cholesterol levels of the double knockout mice were also greater than those of the apoE knockout animals. Despite this lipid profile, there was a significant approximately 70% decrease in atherosclerotic disease area in double knockout mice on a regular diet. Immunohistochemistry and protein blot studies revealed increased EL expression in the atherosclerotic aortas of the apoE knockout animals. An observed decrease in macrophage content in vessels lacking EL correlated with ex vivo vascular monocyte adhesion assays, suggesting that this protein can modulate monocyte adhesion and infiltration into diseased tissues. These data suggest that EL may have indirect atherogenic actions in vivo through its effect on circulating HDL cholesterol and direct atherogenic actions through vascular wall processes such as monocyte recruitment and cholesterol uptake.

    View details for DOI 10.1074/jbc.M406360200

    View details for Web of Science ID 000224505600101

    View details for PubMedID 15304490

  • Treadmill scores in elderly men JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Lai, S., Kaykha, A., Yamazaki, T., Goldstein, M., Spin, J. M., Myers, J., Froelicher, V. F. 2004; 43 (4): 606-615

    Abstract

    This study seeks to further characterize the role of exercise testing in the elderly for prognosis and diagnosis of coronary artery disease.Recent exercise testing guidelines have recognized that statements regarding the elderly do not have an adequate evidence-based quality because the studies they are based on have limitations in sample size and design. The Duke Treadmill Score has been recommended for risk stratification, but recent evidence has suggested that it does not function in the elderly.The study population consisted of male veterans (1872 patients >or=65 years; 3798 patients <65 years) who underwent routine clinical exercise testing with a mean follow-up of six years. A subset who underwent coronary angiography as clinically indicated (elderly, n = 405; younger, n= 809) were included. The primary outcome for all subjects was cardiovascular mortality with coronary angiographic findings as the outcome in those selected for angiography.In survival analysis, exercise-induced ST depression was prognostic in both age groups only when cardiovascular death was considered as the end point. Peak metabolic equivalents were the most significant predictor for both age groups only when all-cause death was considered as the end point. New age-specific prognostic scores were developed and found to be predictive for cardiovascular mortality in the elderly. Moreover, in the angiographic subset of the elderly, a specific diagnostic score provided significantly better discrimination than exercise ST measurements alone. For any new score, there is a need for validation in another elderly population.The mortality end point affected the choice of prognostic variables. This study demonstrates that exercise test scores can be helpful for the diagnosis and prognosis of coronary disease in the elderly.

    View details for DOI 10.1016/j.jacc.2003.07.051

    View details for Web of Science ID 000188944600017

    View details for PubMedID 14975471

  • Retinal evaluation of patients on chronic amiodarone therapy RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Shaikh, S., Shaikh, N., Chun, S. H., Spin, J. M., Blumenkranz, M. S., Marmor, M. F. 2003; 23 (3): 354-359

    Abstract

    To determine whether retinal electrophysiologic changes can be detected and correlated with funduscopic findings in patients with the long-term use of amiodarone.Eleven patients ranging in age from 52 to 67 years were recruited from the Stanford University Medical Center Department of Cardiology for ophthalmologic examination. Patients had received amiodarone at various dosages ranging from 100 to 800 mg daily for at least 15 months. Clinical indications for the use of amiodarone included atrial fibrillation, ventricular arrhythmias, and congestive heart failure. All patients underwent retinal electrophysiology studies (full-field and multifocal electroretinograms) in addition to a complete ophthalmologic examination and fluorescein angiography.No patients were found to have significant vision loss. Funduscopic examination and fluorescein angiography showed mild age-related changes in four patients, three of whom had nonspecific foveal pigmentary alterations. Multifocal and full-field electroretinograms were mostly unremarkable, and the mildly subnormal findings in a few patients showed no consistent pattern to suggest a toxic cause. Dosage, duration of amiodarone exposure, patient age, and underlying cardiac disease did not appear to correlate with these findings.No significant adverse retinal funduscopic changes or electrophysiologic effects could be correlated with amiodarone exposure in this small series of patients. Routine electrophysiologic and funduscopic screening of patients receiving amiodarone does not seem warranted, although future prospective controlled studies may be required to exclude the possibility of progressive abnormalities in patients with preexisting age-related macular degeneration.

    View details for Web of Science ID 000183932600011

    View details for PubMedID 12824836

  • Early use of statins in acute coronary syndromes. Current atherosclerosis reports Spin, J. M., Vagelos, R. H. 2003; 5 (1): 44-51

    Abstract

    This review examines the use of statin medications early in the clinical course of acute coronary syndrome (ACS). Available data demonstrate that there are clear clinical benefits to this practice. Numerous previous studies have documented the primary and secondary benefits of statins in the prevention of coronary events. Recent trials show that when statins are used during hospital admissions for ACS, patients experience decreased recurrent myocardial infarction, lower death rates, and fewer repeat hospitalizations for ischemia or revascularization. Several studies suggest that the positive effects of statins on plaque stabilization, inflammation, thrombosis, and endothelial function may be independent of lipid levels. There is also an emerging view that beneficial lipid-lowering with statins in high-risk patients has no lower limit. This information suggests that all patients admitted for ACS should be treated with statins, regardless of cholesterol levels.

    View details for PubMedID 12562542

  • Early use of statins in acute coronary syndromes. Current cardiology reports Spin, J. M., Vagelos, R. H. 2002; 4 (4): 289-297

    Abstract

    This review examines the use of HMG-CoA reductase inhibitor (statin) medications early in the clinical course of acute coronary syndrome. Available data demonstrate that there are clear clinical benefits to this practice. Numerous previous studies have documented the primary and secondary benefits of statins in the prevention of coronary events. Recent trials show that when statins are used during hospital admissions for acute coronary syndrome (ACS), patients experience decreased recurrent myocardial infarction, lower death rates, and fewer repeat hospitalizations for ischemia or revascularization. Several studies suggest that the positive effects of statins on plaque stabilization, inflammation, thrombosis, and endothelial function may be independent of lipid levels. There is also an emerging view that beneficial lipid-lowering with statins in high-risk patients has no lower limit. This information suggests that all patients admitted for ACS should be treated with statins, regardless of cholesterol levels.

    View details for PubMedID 12052268

  • The prognostic value of exercise testing in elderly men AMERICAN JOURNAL OF MEDICINE Spin, J. M., PRAKASH, M., Froelicher, V. F., Partington, S., Marcus, R., Do, D., Myers, J. 2002; 112 (6): 453-459

    Abstract

    Our purposes were to compare the responses to exercise testing in elderly (> or =65 years of age) and younger men, and to investigate whether exercise testing has similar prognostic value in the two age groups.We included all elderly (n = 1185) and younger (n = 2789) male veterans without established coronary heart disease who underwent routine clinical exercise testing between 1987 and 2000 at two academically affiliated Veteran's Affairs medical center laboratories. Measurements included a standardized medical history, exercise testing, and all-cause mortality.Compared with younger patients, elderly patients achieved a lower workload (a mean [+/- SD] of 7 +/- 3 vs. 10 +/- 4 metabolic equivalents [METs], P <0.001) and were more likely to have abnormal ST depression (27% [n = 324] vs. 16% [n = 436], P <0.001). During the mean follow-up of 6 years, annual mortality was twice as high among elderly patients as among younger patients (4% vs. 2%, P <0.001). The only exercise test variable that was associated significantly with time to death in both age groups was maximal METs achieved: each 1 MET increase in exercise capacity was associated with an 11% reduction in annual mortality. Exercise-induced ST depression was more common in those who subsequently died, but was not an independent predictor of mortality.In elderly men, exercise testing provided prognostic information incremental to clinical data. Achieved workload (in METs) was the major exercise testing variable associated with all-cause mortality. Its prognostic importance was the same in elderly as in younger men.

    View details for Web of Science ID 000175126000003

    View details for PubMedID 11959055

  • Abnormal ECG after extensive maxillofacial surgery HOSPITAL PRACTICE Spin, J., Hancock, E. W. 1999; 34 (11): 27-28

    View details for Web of Science ID 000083062900003

    View details for PubMedID 10887427

  • CRYOELECTRON MICROSCOPY OF LOW-DENSITY-LIPOPROTEIN IN VITREOUS ICE BIOPHYSICAL JOURNAL Spin, J. M., Atkinson, D. 1995; 68 (5): 2115-2123

    Abstract

    In this report, images of low density lipoprotein (LDL) in vitreous ice at approximately 30 A resolution are presented. These images show that LDL is a quasi-spherical particle, approximately 220-240 A in diameter, with a region of low density (lipid) surrounded by a ring (in projection) of high density believed to represent apolipoprotein B-100. This ring is seen to be composed of four or five (depending on view) large regions of high density material that may represent protein superdomains. Analysis of LDL images obtained at slightly higher magnification reveals that areas of somewhat lower density connect these regions, in some cases crossing the projectional interiors of the LDL particles. Preliminary image analysis of LDL covalently labeled at Cys3734 and Cys4190 with 1.4-nm Nanogold clusters demonstrates that this methodology will provide an important site-specific marker in studies designed to map the organization of apoB at the surface of LDL.

    View details for Web of Science ID A1995RH65800052

    View details for PubMedID 7612855

Conference Proceedings


  • Nicotine Accelerates the Expansion of Abdominal Aortic Aneurysms in Mice; A Potential Role for miR-21 and miR-26a Maegdefessel, L., Azuma, J., Spin, J. M., Deng, A., McConnell, M. V., Dalman, R. L., Tsao, P. S. LIPPINCOTT WILLIAMS & WILKINS. 2010

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