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Research Program

Welcome to our Cardiology Research site

HeLa6_Combined
HeLa cells immunostained with anti-fortilin and anti-p53 antibodies

The Division of Cardiology at UTMB Health pursues academic cardiology consisting of exemplary patient care, education, and research. Our research is both clinical and basic. Through clinical research we test new medications and therapies for future clinical use. Also, included in clinical research is translational research where innovation and discovery at bench is brought to bedside. Basic research in the Division of Cardiology focuses on fortilin, a novel anti-apoptotic molecule that has been implicated in atherosclerogenesis. We invite you to discover more about our research through this site.

Clinical and Translational Research Effort
at Division of Cardiology

Optical coherence tomography (OCT) showing the formation of platelet-rich thrombi within a stent
Optical coherence tomography (OCT) showing
the formation of platelet-rich thrombi within a stent

The Division of Cardiology has actively participated in industry-initiated clinical trials. With a robust and local IRB that meets twice a month, our team has constantly secured IRB approval for clinical trials within 8 weeks. Our hospital uses EPIC as electronic medical record (EMR), with strong search and query functions. Our hospital - John Sealy Hospital - is a university hospital where all patients are seen by our clinical faculty members, thus making the screening of patients and implementation of protocols seamless. Staffed by two full-time, cardiology-specifically trained clinical coordinators, our division has had an excellent track record for enrollment and retention of patients. We have been ranked #5 for PreSERVE AMI (NCT01495364), #13 for ILUMIEN-1 (NCT01663896), and #7 for RELAX (NCT02064868). Please contact Dr. Ken Fuijse (Ken.Fujise@utmb.edu), Director of Clinical Cardiology Research for any questions.

Clinical Research Office
Location: John Sealy Annex 5.110-A (Mail Route 0553)
Telephone: 409.747.1892
Fax: 409.747.1811

Staff at Clinical Research Office
Janet Allen, RN
Clinical Research Nurse/Coordinator
Pager: 409.645.5001

Sharon Ronald, MS
Sr. Clinical Research Coordinator
Pager: 409.643.0631

Clinical Research Projects and Trials


SOLID-TIMI52 (The Stabilization of Plaques using Darapladib-Thrombolysis in Myocardial Infarction 52 Trial).
 
ClinicalTrials.gov ID: NCT01000727
Sponsoring Agency: GlaxoSmithKline
Date: 6/1/2010 - Current
Synopsis: This study is evaluating the safety and tolerability of a new drug in patients admitted with acute coronary syndrome (ACS). Patients will include those with unstable angina, STEMI and NSTEMI. It is felt the study drug will promote stability of plaque in the coronary arteries and reduce vascular inflammation in patients with coronary heart disease. Length of study participation is 36 months.

IMPROVE-IT (IMProved REduction of Outcome: Vytorin Efficacy International Trial (IMPROVE IT) A Multicienter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (ezetimibe/simbastatin)vs Simbastatin Monotherapy in High Risk Patients Presenting with Acute Coronary Syndrome).
 
ClinicalTrials.gov ID: NCT00202878
Sponsoring Agency: Schering Plough
Date: 05/16/2006 - Current
Synopsis: The safety and clinical benefit of Vytorin compared to simvastatin in patients admitted with ACS, either unstable angina or acute MI, are being evaluated in this study. Enrollment of new subjects is now closed and currently enrolled patients will be followed through the length of the study.

PreSERVE AMI (A Prospective Randomized Double Blinded Placebo Controlled Phase II Trial of Intra-coronary Infusion of AMR-001, a Bone Marrow Derived Autologous CD34+ Selected Cell Product, in Patients with Acute Myocardial Infarction).
 
ClinicalTrials.gov ID: NCT01495364
Sponsoring Agency:AMORCYTE, INC.
Date: 03/21/2012 - Current
Synopsis: Evaluation of safety and efficacy of intracoronary infusion of AMR-001 or placebo on myocardial perfusion and function after STEMI. Patients will undergo mini-bone marrow harvest 4-9 days after stent placement. Bone marrow will be processed to isolate stem cells. Stem cells or placebo will be infused into the area of infarct within 72 hours of harvest. Follow-up period: 3 years.

ILUMIEN (Observational Study of Optical Coherence Tomography (OCT) in Patients Undergoing Fractional Flow Reserve (FFR) and Percutaneous Coronary Intervention).
 
ClinicalTrials.gov ID: NCT01663896
Sponsoring Agency: St. Jude Medical
Date: 11/01/2012 - Current
Synopsis: To define and evaluate Optical Coherence Tomography (OCT) stent guidance parameters through prospective data collection in PCI procedures of de novo lesions. Enrollment will include individuals undergoing PCI for treatment of coronary artery disease.

CANTOS (A Randomized, Double-Blind, Placebo-Controlled, Event-Driven Trial of Quarterly Subcutaneous Canakinumab in the Prevention of Recurrent Cardiovascular Events Among Stable Post-Myocardial Infarction Patients With Elevated hsCRP).
 
ClinicalTrials.gov ID: NCT01327846
Sponsoring Agency: Novartis Pharmaceuticals Corporation
Date: 06/01/2012 - Current
Synopsis: Demonstrate superiority of canakinumab over placebo in preventing major cardiovascular events in stable post MI patients with elevated hsCRP receiving standard of care treatment. Patients will include those with MI at least one month prior to study entry. Follow-up: approximately 48 months.

Basic Science Research Effort at Division of Cardiology

MRI of a mouse heart after transaortic constriction procedure
MRI of a mouse heart after transaortic constriction procedure

Laboratory Location: Medical Research Building (MRB 7.166)
Laboratory Telephone: 409.772.5870, 5871, 5872, and 5873.

Members of Cardiology Basic Science Research Laboratory

Ken Fujise, MD
Principal Investigator
Professor of Medicine and of Biochemistry and Molecular Biology
E-mail: ken.fujise@utmb.edu
Office: 409.772.4885

Heather Foster
Laboratory Coordinator
Office: 409.772.4885

Decha Pinkaew, Ph.D.
Research Scientist

Nattaporn Wanachottrakul, Ph.D.
Postdoctoral Fellow

Abhijnan Chattopadhyay, Ph.D.
Postdoctoral Fellow

Patuma Sinthujaroen, Ph.D.
Postdoctoral Fellow

Preedakorn Chunhacha, Ph.D.
Postdoctoral Fellow

Hasseri B. Halim, Ph.D.
Postdoctoral Fellow

Research Projects

computer-assisted virtual docking of fortilin (green) and the sequence specific DNA binding domain of p53 (red)
A computer-assisted virtual docking of fortilin (green) and
the sequence specific DNA binding domain of p53 (red)

Fortilin

Fortilin and Atherosclerosis:
Atherosclerosis is the leading cause of death in the US. Despite extensive use of treatment regimens aimed at optimizing lipid levels, about half of patients with acute myocardial infarction seen in emergency departments have normal lipid profiles, suggesting that the eradication of atherosclerosis and its complications calls for not only statin therapy but also the development of innovative treatment regimens. Since its inception in 1997, Fujise's lab has studied fortilin and its role in vascular biology. The lab first reported that fortilin is an anti-apoptotic molecule that interacts with MCL1, an anti-apoptotic Bcl-2 family member protein critical for macrophage survival. Furthermore, the lab showed that fortilin message levels are significantly higher in patients with coronary artery disease (CAD); and that atherosclerotic plaques over express fortilin. In addition, the lab discovered that DHA, an artemisinin derivative, binds to and facilitates degradation of fortilin. In the laboratory, we explore (a) the basic mechanism of action of fortilin, (b) the role of fortilin in atherosclerogenesis, (c) the use of fortilin as a biomarker of coronary artery disease, (d) the use of DHA-derivatives for the prevention and treatment of atherosclerosis. Research on fortilin and atherosclerosis is currently supported by NHLBI R01 (2013-2018), American Heart Association Grant-in-Aid (2011-2013) and others.

BBA-CLINICAL Graphical Abstract.jpg

Fortilin As a Biomarker of In Vivo Apoptosis
Billions of cells undergo apoptosis each day in the average normal adult. The ability to readily assess the degree of apoptosis in human diseases is hampered by the lack of sensitive and specific serum biomarkers of apoptosis. Fortilin is a novel prosurvival molecule that protects cells against various noxious stimuli. While fortilin is secreted into the extracellular space under certain conditions, the relationship between the serum concentration of fortilin and the presence and extent of apoptosis in vivo remains unknown. Using a newly developed fortilin ELISA system, we have shown that fortilin exists in the normal human and mouse circulation. In addition, fortilin serum levels are significantly elevated in patients with solid cancer, in response to anti-cancer chemo- or radiation therapy. The elevation of fortilin serum levels is more robust and sensitive than that of such previously-reported serum biomarkers of apoptosis as fragmented cytokeratin-18, cytochrome c, and nucleosomal DNA. Further, targeted apoptotic liver damage induced by Jo2 anti-Fas (CD95) antibody consistently and significantly increases serum fortilin levels in C57BL/6J mice. Finally, when challenged by anti-human-Fas IgM antibody, Jurkat leukemic T cells apoptose and release fortilin into the medium before plasma membrane integrity becomes compromised. Conclusions: Taken together, our research suggest that serum fortilin levels reflect the degree and extent of apoptosis occurring in vivo. Fortilin is a viable serum biomarker of in vivo apoptosis and can be utilized to noninvasively assess the status of in vivo apoptosis in humans.

Fortilin and Cancer
Tumor suppressor protein p53 keeps us free of cancer when it is function. Mutated p53 genes are seen in more than 50% of all human cancers, making them the most frequently observed genetic derangement in human cancer. At a molecular level, the ability of p53 to eliminate cancerous cells relies on its ability to induce apoptosis, through either the transcriptional activation of proapoptotic genes such as Noxa , PUMA, and Bax or the direct transcription-independent activation of Bax on mitochondria. Growing cancers manage to keep p53 in check either by mutating the p53 gene itself or by expressing p53 inhibitors such as Mdm2. Recently, our laboratory reported that fortilin is upregulated in many human malignancies and that fortilin binds specifically to the sequence-specific DNA binding domain of p53. The interaction of fortilin with p53 blocks p53-induced transcriptional activation of Bax. Fortilin, but not a double point mutant of fortilin lacking p53 binding, inhibits p53-dependent apoptosis. Furthermore, cells with wild-type p53 and fortilin, but not cells with wild-type p53 and the double-mutant of fortilin lacking p53 binding, fail to induce Bax gene and apoptosis, leading to the formation of large tumors in athymic mice. Fortilin is a novel p53-interacting molecule and p53 inhibitor. Fortilin thus is a logical molecular target in cancer therapy. Efforts to identify small molecule inhibitors of fortilin is underway in our laboratory.

HPV and Heart Disease

Inflammation contributes to the development and progression of atherosclerosis. In order to examine the association between human papillomavirus (HPV) with cardiovascular disease (CVD), the data from the National Health and Nutritional Examination Survey (2003-2006, 2450 women) was investigated. A total of 60 females (39 women were HPV DNA positive, whereas 21 were negative) had coronary artery disease. Presence of vaginal HPV DNA was associated with CVD. Odds ratio (OR) of CVD comparing women with presence of vaginal HPV DNA to those without was 2.30 (95% confidence interval [CI]: 1.27 to 4.16) after controlling for demographics, health/sex behaviors, medical comorbidities, cardiovascular risk factors, and management. At the same level of adjustment, OR of CVD comparing women with cancer-associated HPV types to those with negative HPV was 2.86 (95% CI: 1.43 to 5.70). HPV infection, especially cancer-associated oncogenic types, is associated with CVD among women. (J Am Coll Cardiol 2011;58:2001-6) Further studies are necessary to establish the causal relationship between HPV infection and atherosclerogenesis.

Morelloflavone

Oil-Red-O en face atherosclerosis assay on a mouse aorta
Oil-Red-O en face
atherosclerosis assay
on a mouse aorta

Garcinia dulcis, a plant that belongs to the Guttiferae family, is widely distributed in Thailand, and other Southeast Asian countries. It has been used in traditional medicine for centuries to treat various inflammatory conditions. The main constituent of the plant is morelloflavone, a biflavonoid comprising two covalently linked flavones-apigenin and luteolin. The Fujise Lab tested if morelloflavone prevented post-angioplasty restenosis and atherosclerosis, using mouse models of post-angioplasty restenosis and atherosclerosis, respectively. It was shown that morelloflavone blocks both restenosis and atherosclerosis through the blockade of vascular smooth muscle cell migration from the media to the intima.

Patents

  1. Methods And Compositions Relating To Fortilin, An Anti-Apoptotic Molecule, And Modulators Of Fortilin,USPO: 10/021,753 (Awarded)
  2. Composition and Method for Treatment and Prevention of Restenosis, USPO: 10/448,664 (Awarded)
  3. Reducing Myocardial reperfusion injury by the combination therapy of protein kinase A activation and beta-1-adrenergic receptor blockade (US Patent Pending, 12/997,485)
  4. Uses of morelloflavone (US Patent Pending, 12/931,310)

Pertinent Publications

  1. Sinthujaroen P, Wanachottrakul N, Pinkaew P, Petersen J, Phongdara A, Sheffield-Moore M, Fujise K. Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo. Biochimica et Biophysica Acta Clinical (BBA Clinical) 2014 in press
  2. Pinkaew D, Le RJ, Chen Y, Eltorky M, Teng BB, Fujise K. Fortilin Reduces Apoptosis in Macrophages and Promotes Atherosclerosis. American journal of Physiology Heart and Circulatory Physiology 2013. PMID 24043250
  3. Chen Y, Fujita T, Zhang D, Doan H, Pinkaew D, Liu Z, Wu J, Koide Y, Chiu A, Lin CJC, Chang JY, Ruan KH, Fujise K: The physical and functional antagonism between tumor suppressor protein p53 and fortilin, an anti-apoptotic protein. Journal of Biological Chemistry 2011. 286; 37: 32575-85. PMID: 21795694
  4. Kuo HK, Fujise K: Human papillomavirus and cardiovascular disease among U.S. women in the National Health and Nutrition Examination Survey, 2003-2006. Journal of American College of Cardiology 2011: 58: 2001-6. PMID: 22032713
  5. Pinkaew D, Hutadilok-Towatana N, Teng BB, Mahabusarakam W, Fujise K. Morelloflavone, a biflavonoid inhibitor of migration-related kinases, ameliorates atherosclerosis in mice. American Journal of Physiology-Heart and Circulation. 2011. In press
  6. Koide Y, Tonganunt M, Kato Y, and Fujise K. Fortilin-deficiency causes embryonic lethality through the overactivation of BMP4 Pathway. Biochimica et BiophysicaActa 2009;1790:326-38 PMID: 2695948
  7. Graidist P, Yazawa M, Tonganunt M, Nakatomi A, Lin CC, Chang J, Phongdara A, Fujise K. Fortilin binds Ca2+ and blocks Ca2+-dependent apoptosis in vivo. Biochemical Journal 2007; 408(2):181-91. PMID: 2267342
  8. Graidist P, Fujise K, Wanna W, Sritunyalucksana K, Phongdara A: Establishing A Role For Shrimp Fortilin In Preventing Cell Death. Aquaculture 2006; 255:157-164. ISSN: 0044-848
  9. Graidist P, Phongdara A, and Fujise K: Anti-apoptotic protein partners fortilin and MCL1 independently protect cells from 5-FU-induced cytotoxicity: Fortilin-MCL1 interaction in apoptosis. Journal of Biological Chemistry 2004; 279:40868-40875. PMID: 15262975
  10. Mnjoyan ZH, Dutta R, Zhang D, Teng BB, and Fujise K: Paradoxical upregulation of tumor suppressor protein p53 in serum-stimulated vascular smooth muscle cells. Circulation 2003; 108:4:464-471. PMID: 12860918
  11. Tulis DA, Mnjoyan ZH, Schiesser R, Shelat HS, Zoldehelyi P, Fujise K: Adenoviral gene transfer of fortilin attenuates neointima formation through suppression of vascular smooth muscle cell proliferation and migration. Circulation 2003; 107:98-105. PMID: 12515750
  12. Zhang D, Li F, Mnjoyan ZH, Weidner D, Fujise K: Physical and functional interaction between MCL1 and fortilin. The potential role of MCL1 as a fortilin chaperone. Journal of Biological Chemistry 2002; 227 (40):37430-37438. PMID: 12149273
  13. Li F, Zhang D and Fujise K: Characterization of fortilin, a novel anti-apoptotic protein. Journal of Biological Chemistry 2001;276(50):47542-47549. PMID: 11598139
  14. Fujise K, Zhang D, Liu JL and Yeh ETH: Regulation of apoptosis and cell cycle progression by MCL1. Differential role of MCL1. Journal of Biological Chemistry 2000, 275(50):39458-65. PMID: 10978339
  15. Gong L, Kamitani T, Fujise K, Caskey LS, Yeh ETH: Preferential interaction of sentrin with a ubiquitin-conjugating enzyme, Ubc9. Journal of Biological Chemistry: 1997, 272(45)28198-201. PMID: 9353268
  16. Fujise K, Stacy L, Beck P, Yeh ETH, Chuang A, Brock TA, Willerson JT: Differential effects of endothelin receptor activation on cyclic flow variations in rat mesenteric arteries. Circulation 1997; 96(10);3641-6. PMID: 9396466
  17. Fujise K, Revelle M, Stacy L, Willerson JT, Beck P: A tPA/P-selectin fusion protein is an effective thrombolytic agent. Circulation 1997; 95:715-722. PMID: 9024162
The UTMB Truman Graves Blocker, Jr. Medical Research Building
The UTMB Truman Graves Blocker, Jr. Medical Research Building that houses the cardiology research laboratory was built in 1991.

 

The department of internal medicine is developing evidence based clinical protocols which will be available in EPIC (as order sets) for use when admitting patients with these diagnoses. Their AIM is to standardize care and decrease length of stay and readmission rates.

Currently available protocols are:
  • CAP - Community Acquired Pneumonia Orderset
  • Congestive Heart Failure (CHF)
  • Chronic Obstructive Pulmonary Disease (COPD)
  • Diabetic Ketoacidosis Adult, ICU
  • General Medicine Admission
  • Immunodeficiency Flow Panel
  • MICU/CCU Admission Order Set
  • Oral Analgesic Medicaitons
  • Parenteral Opioids
  • Sepsis, Adult ICU
  • 111 - Stroke Alert
  • 112 - Stroke Activation
  • 300086 - Stroke Floor Admission
  • 3000000001 -  Stroke Critical care without tPA
  • 300088 Stroke - Transfer from Critical care to floor
  • 3004002 - Stroke Discharge

All protocols can be found in the EPIC order set section.

» For more information

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The department of Internal Medicine has a large role in the Meaningful Use Initiative. Our participation is key for the success of the initiative. Please visit the meaningful use website for important communication and updates from the Meaningful Use Initiative.

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