universitas hasanuddin · behoudens de in of krachtens de auteurswet van 1912 gestelde...

Heart and Blood Vessels

Development, Disease and State of the Art Therapies

Module coordinators: Prof. Dr. van Zonneveld Prof. Dr. D.E. Atsma Drs. R.G. de Bruin [email protected] [email protected] [email protected]

M O D U L E B O O K

Bachelor Medicine, third year Course year 2014-2015

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Contents Module committee and teachers 1 Introduction 3 Module overview 5 Overall learning objectives 6 Tests and examinations 7

Specification 8 Detailed descriptions 9 Additional tests 9 Re-examinations 10 Additional tests and feedback 10 Prerequisites 11

Themes 13 Week 1 Development and anatomy of the cardiovascular system, molecular medicine 14 Week 2 Physiology of heart and vessels 20 Week 3 Haemostasis and thrombosis 25 Week 4 Macrovascular disease: atherosclerosis 1/2 31 Week 5 Macrovascular disease: atherosclerosis 2/2 38 Week 6 Clinical diagnosis and therapy in cardiac syndromes 43 Week 7 Vascular surgery and peripheral arterial disease 48 Week 8 Microvascular disease: renal and cardiac 53 Week 9 Innovative therapeutic strategies in CVD 58 Week 10 Case report 62 Appendix 1: Assessment form 64 Appendix 2: Guidelines Case Report 65 Appendix 3: Guidelines report score 67

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Module committee and teachers

Module coordinators

Prof. Dr. A.J. van Zonneveld (Anton-Jan) Discipline: Experimental Vascular Nephrology [email protected] Room C7-29 Telephone: 071-5265196

Prof. Dr. D.E. Atsma (Douwe) Discipline: Interventional Cardiology [email protected] Room C5-32 Telephone: 071-5261273

Drs. R.G. de Bruin (Ruben) Discipline: Experimental Vascular Medicine [email protected] Room C7-36 Telephone: 071-5268136

Module committee: Week coordinators

Prof. dr. D.E. Atsma, Dr. D.A. Pijnappels, Prof. dr. H.C.J. Eikenboom, Prof. dr. M.V. Huisman, Prof. dr. P.H. Reitsma, Prof. dr. M.J.T.H. Goumans, Prof. dr. P.H.A. Quax, Prof. dr. J.F. Hamming, Prof. dr. P.C.N. Rensen, Prof. dr. A.M. Pereira, Prof. dr. H. Pijl, Prof. dr. Ir. J.A.P. Willems van Dijk and Prof. dr. A.J. van Zonneveld. Teachers Department of Nephrology Dr. H.C. de Boer Dr. Ir. R. Bijkerk Dr. M.A. Engelse Prof. H. de Fijter Dr. A. Gaasbeek Prof. Dr. E.J.P. de Koning M. Moses Prof. A.J. Rabelink Dr. M.E.J. Reinders Dr. T.C. Rothuizen Dr. J.I. Rotmans Dr. E.P. van der Veer Y. Abdallah

Department of Cardiology Dr. R. Alizadeh Dehnavi Dr. S.L.M.A. Beeres Dr. B.O. Bingen Dr. G. de Grooth Prof. J.W. Jukema Dr. F. van der Kley Dr. P. Steendijk Dr. S.A.I.P. Trines Dr. H.F. Verwey Dr. A.A.F. de Vries Prof. K. Zeppenfeld

mailto:[email protected]



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Department of Anatomy & Embryology Prof. Dr. C.L. Mummery J.C. van Munsteren Prof. Dr. M.C. de Ruiter L.J. Wisse Department of Molecular Cell Biology Prof. Dr. M.J.T.H. Goumans Dr. A.M. Smits Department of Endocrinology Dr. J.F.P. Berbée Dr. N.R. Biermasz Drs. M.R. Boon Dr. O.C. Meijer Dr. D. Mook Dr. Y. Wang Department of Thrombosis & Haemostasis Dr. M.H.A. Bos Dr. F.A. Klok Dr. F.J.M. van der Meer Dr. H.H. Versteeg Dr. B.J.M. van Vlijmen

Department of Human Genetics Dr. V.J.A. Van Harmelen Dr. Ir. J.B. van Klinken Department of Surgery Dr. J.H.N. Lindeman Dr. A.Y. Nossent Dr. A. Schepers Dr. Ing. M.R. de Vries Dr. C.Y. Wong Department of Clinical Epidemiology Dr. Ir. R. de Mutsert LACDR, Biopharmaceutics Prof. Dr. J. Kuiper Dr. P. Vulto Department of Pathology Dr. H. Baelde Department of Neurology M.J.H. Wermer

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Introduction

In ten consecutive weeks the students will be introduced to the most current concepts in the pathogenesis, diagnosis and therapy of the most common forms of cardiovascular disease. The course will start with a basic introduction into the anatomy, physiology and haemostatic mechanisms in the cardiovascular system. Next, the students will be introduced in the pathogenesis of macrovascular disease (e.g. atherosclerosis, coronary artery disease, ischemic peripheral disease) and microvascular diseases (e.g. ischemic heart disease, heart failure). Current options for diagnosis and therapy will be discussed as well as the current approaches in epidemiology and the use of biomarkers for cardiovascular disease. A special feature of this ½ minor is that we will also aim to update the students on various “molecular medicine” approaches that are currently employed to develop novel experimental therapies. Last days of the week will be devoted to introduce the students to innovative preclinical (animal) models that are used by the members of the profile area to study the pathophysiology and experimental therapies of the topic of the week. Where relevant, current insights in molecular backgrounds of the innovative strategies will be reviewed. At the beginning of the course each of the students will receive a case description of a patient that typifies the cardiovascular disease states that are addressed in the consecutive weeks (e.g. acute coronary syndrome, hearth failure, diabetes with cardiovascular complications etc.). Following every weekly course, the students are requested to write a blog in which they list and discuss the relevance of the topics reviewed in the past week to the case they were assigned to study. These blogs will be assessable to dedicated teachers (teachers will be assigned to provide feedback on the blog of a limited number of students) who will give short comments or feedback that can be helpful to the student and helps to make sure they do not forget to update their blogs). In the course of the ½ minor this blog will accumulate into a document that includes aspects of the etiology, epidemiology, pathogenesis diagnosis and therapeutic approaches that are relevant to the individual cases of the particular student. In the final week the student will be asked to write a comprehensive case report including diagnosis, etiology, potential treatment, prognosis and future therapeutic options. This case report will serve a main part of the examination process.

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Module overview

Half minor: Heart and blood vessels: development, diseae and state of the art therapies Atsma, van Zonneveld, de

Bruin

Week 1 Development and anatomy of the cardiovascular system, molecular medicine Atsma, van Zonneveld, de Brui2-5 Sept

Embryology of the cardiovascular system de RuiterGenetic variations in cardiovascular development van Wisse, van MunsterenEndothelial cell biology Van Gils, RabelinkMechanisms in vascular maintenance and repair van Zonneveld, de BoerThe basics of molecular cell biology and gene expression van der VeerThe technique of PCR de Bruin, van Vlijmen

Week 2 Physiology of heart and vessels Atsma, Pijnappels8-12 sept

Heart function Pijnappels, de Vries, SteendijkElectrophysiology Ypey, Trines, Feola, Blood pressure regulation and hypertension Rotmans, JangsangthongExperimental therapeutic approaches in hypertension Majumder, Askar

Week 3 Hemostasis and thrombosis Eikenboom, Huisman, Reitsma15-19 sept

Pathophysiology of Blood Coagulation VersteeghClinical and laboratory diagnostics in hemostasis Huisman, Bos,Hemophilia and clinical management van der Meer, KlokAcute severe derangement of hemostasis van VlijmenExam week 1-3

Week 4 Macrovascular disease: atherosclerosis 1 Rensen, Willems van Dijk, Pereira

22-26 septDyslipidemia Jukema, Pijl, HuismanObesity, Metabolic syndrome and Type 2 diabetes Van Harmelen, KuiperPathogenesis of atherosclerosis BoonInflammation, Risk factors

Week 5 Macrovascular disease: atherosclerosis 2 Rensen, Willems van Dijk29 sept-3 oct

Cerebrovasculair incident Wermer, van WalderveenGenetics and epidemiology Mutsert, KruytCentral mechanisms Biermasz, van ZonneveldRationale and design of the NEO study Mook, van Klinken

Week 6 Clinical diagnosis and therapy Atsma, Pijnappels13-17 oct

Acute coronary syndrome and heart failure Jukema, Beeres,SteendijkClinical management of ACS Verwey, de GroothCardiac arrhythmia's Alizadeh, ZeppenfeldConventional therapies (angioplasty, bypass, medication) van der Veer, de VriesExperimental models for neointimal hyperplasia BingenExam week 4-6

Week 7 Vascular surgery and peripheral artery disease Hamming, Quax13-17 oct

Introduction in vascular surgery Schepers, de VriesPost-interventional vascular remodeling LindemanAneurysma's Rotmans, RothuizenVascular access in CKD Chun Yu Wong, Nossent

Week 8 Microvascular disease Goumans20-24 oct

Cardiovascular complications of type 1 diabetes De Koning, van ZonneveldPathophysiology of Diabetic Nephropathy de FijterCardiac manifestations of microvascular disease GaasbeekMicrovacular rarefaction and fibrosis BaeldeExperimal animal models in microvascular disease Bijkerk

Week 9 Innovative therapeutic strategies Atsma27-31 oct van Zonneveld

Concept of personalized medicineModels for drug testing in CVD MummeryInnovative therapies for the heart Vulto, ReindersInnovative therapies for the heart and beyond GoumansTransplantation of islets to treat hyperglycemia EngelseFinal exam

Week 10 Case Report Atsma, van Zonneveld3-7 nov Write and submit your case report

Present case report

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Overall learning objectives

1. Evaluate the pathogenic molecular mechanism(s) that might underlie the complaints of a patient diagnosed with a cardiovascular disorder and relate these pathogenic mechanisms to signs and symptoms

2. Be able to motivate and interpret conventional and innovative diagnostic plans that could be applied based on a differential diagnosis

3. Develop a “state of the art” therapeutic plan based on the results from diagnostic tests and

corresponding diagnosis and describe the method to check the effect of the intervention

4. Critically assess and communicate recent high impact publications in cardiovascular medicine with regard to methodology, pit falls and limitations.

5. Explain the molecular mechanisms underlying innovative therapeutic strategies and relevant

experimental animal models for cardiovascular disease

6. Be able to make an evaluation of the feasibility, clinical potential and societal and legislative relevance of novel innovative therapeutic strategies for specific patient cases.

7. Write a case-report with emphasis on the integration of conventional and innovative diagnostics and

therapeutic strategies.

8. Identify relevant literature related to the topics of the course and the selected case report.

9. Demonstrate the ability to implement feedback to the blog and case report.

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Tests and examinations

Test matrix Assignment Paper

presentations Knowledge test 1, 2

Final knowledge test

Cumulative blog Case report

Type of exam Oral presentation Written exam

over week 1-3 and 4-6 All open questions.

Written exam over week 1-9 All open questions.

Up to 500 word reflections of relevance weekly topics to case descriptions

Written case description (see below)

Area Academic skills, communication, collaboration

Knowledge

Knowledge, Academic skills

Knowledge, Academic skills, communication

Knowledge, Academic skills, communication

Time Week 2,4,5,6,7

Week 3,6

Week 9

Week 2,3,4,5,6,7,8 and 9

Week 10

Length During 1.5 hr workgroups

1.5 hr 1.5 hr 2 hr 20 hour preparation

Weight (% of total)

Pass/Fail

25%

25%

Pass/correct and pass

50%

Collaboration Group (5P) Individual basis Individual basis Individual basis Individual basis

Assessed by Minor teachers

by teachers by teachers Mentor dedicated to student

Mentor dedicated to student

Number of question

N.a. Open (10) Open (10) N.a. N.a.

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Further specification to learning objectives Type of exam Paper

presentations Knowledge tests (3x)

Cumulative blog

Case report

evaluate the pathogenic molecular mechanism(s) that might underlie the complaints of a patient diagnosed with a cardiovascular disorder and relate these pathogenic mechanisms to signs and symptoms (academic)

X X X X

able to motivate and interpret conventional and innovative diagnostic plans that could be applied based on a differential diagnosis

X X X

develop a “state of the art” therapeutic plan based on the results from diagnostic tests and corresponding diagnosis and describe the method to check the effect of the intervention

X X X

critically assess and communicate recent high impact publications in cardiovascular medicine with regard to methodology, pit falls and limitations (academic, communicator)

X X

explain the molecular mechanisms underlying innovative therapeutic strategies and relevant experimental animal models for cardiovascular disease (academic)

X X X

able to make an evaluation of the feasibility, clinical potential, societal and legislative relevance of novel innovative therapeutic strategies for specific patient cases (academic, communicator)

X

X X

write a case-report with emphasis on the integration of conventional and innovative diagnostics and therapeutic strategies (academic, medical expert, communicator)

X

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identify relevant literature related to the topics of the course and the selected case report. (academic)

X X

demonstrate the ability to implement feedback to the blog and case report (academic, communicator)

X X

Detailed description of tests and examinations Knowledge tests Exam (1; covering week 1-3 and 2; covering week 1-6) consists of 10 open questions based on a pre-evaluated question and answer model. Rating: mark 1-10 Assessed by: at least two minor teachers. Final knowledge test Exam covers the content of the complete course consists of 10 open questions based on a pre-evaluated question and answer model. Rating: mark 1-10 Assessed by: at least two minor teachers. Case report A written case description of 3000-4000 words that describes the differential diagnosis, epidemiology, pathogenesis, therapeutic plan, prognosis and a discussion of potential innovative therapeutic perspectives that are relevant to the case that was handed out to the student in week 2. Where relevant references are included to the published literature. Case descriptions are prepared by the students on an individual basis and are based on the cumulative information and feedback given by the dedicated teacher collected in the weekly blogs (see below). Recommendations and criteria for writing the case description are described in appendix 3. After completion, cases (four different case descriptions are handed out to the students) are discussed with the students in a plenary session by a clinical minor teacher. Rating: mark 1-10 Assessed by: pairs of 3 minor teachers (at least one with a clinical and one with a fundamental background). Assessment criteria: case reports will be evaluated on criteria of clinical, scientific and writing skills. Calculation of overall mark Overal the final mark should be ≥ 5.5 and at least 3 out of 4 elements need to be ≥ 5.5. Knowledge test 1 = 12.5 % Knowledge test 2 = 12.5 % Final knowledge test = 25 % Case report = 50 % Additional tests Paper presentations At five occasions students will be handed out scientific papers related to the topics of the week. In groups of 5 students per group they will study the papers and prepare 10 minute presentations to explain the content and implications of the reported studies/reviews to their fellow students. The papers will be presented by a single student such that every student will get its turn during the course. All students of the presenting group will participate in the ten minute discussion sessions following the presentations. The sessions will be chaired by minor teachers of the week.

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Assessment: pass/fail based on participation and contribution Assessed by: minor teachers of the week Blog In the beginning of week 2 the student will be handed out one of four case descriptions of patients with various forms of cardiovascular disease. At the end of each week the students have to write a blog (up to 500 words per contribution) and report what aspects of the current week are relevant for the case descriptions they have received. The blogs are posted as a shared file in the blackboard module. Assessed by: Each student will get weekly feedback on their blogs by a dedicated mentor who will also coach the student throughout the ten weeks of the course. Assessment: Pass/Fail Presence Presence and participation during the modules of the half minor will be recorded. From the paper presentation session only one out of five can be missed (with prior notice) and should be compensated by an alternative assignment. Absence is only allowed after permission by email of one of the block-coordinators. Re-examinations Knowledge tests In case of insufficient scoring for the knowledge tests a second chance exam will be organized. This will however be only one test that, like the final knowledge test covers the theory and practice of the entire course. The format will be equal to the final knowledge test. The scoring will be based on the knowledge percentages that the students achieved during the regular final knowledge exam. Case report When the submitted case report is insufficient (≤ 5.5) the student will get the opportunity to improve the weaknesses of the report on the basis feedback provided by the teachers that assessed the report. The coordinator will determine the deadline for submitting the modified case report. Additional tests and feedback • Paper presentation and discussion workgroups (week 2, 4, 5, 6 and 7) are selected and supervised in a

way to optimize self-study of the study topic of the week. Feedback will be given on the content and form of the presentations on a group and individual basis. Student should actively participate in the discussions. If not the student will be urged by the teacher to adopt this and will try to get the student involved by direct questions and/or the guidance of discussions among the students. Getting involved in the discussions will train the student to cope with scientific questions and help to learn to evaluate diagnostic and therapeutic plans. These activities are meant to train the students in a way that helps them to write their case reports.

• The weekly blogs are meant as a repeated learning/evaluation activity regarding the study material that is offered that particular week. The fact that the student will have to evaluate what presented weekly issues is/are relevant to their particular case and that they will get feedback on this by their designated personal mentor will help the students to place the presented information in a context.

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Prerequisites (not obligatory to join this minor, but highly recommended) Previous Bachelor modules

Mechanisms of disease 1 & 2 Academic and Scientific Education Vraagstukken Bewegen Vraagstukken Buik Vraagstukken Borst en nier Vraagstukken Geestelijke gezondheid

Place in the curriculum The module will be held in the first 10 weeks of the third year of the Bachelor of Medicine. This half minor will be an overview in the most current concepts in cardiovascular disease and is therefore useful for anyone interested in this particular field of medicine. Study books Kumar, Abbas and Fausto. Robbins and Cotran, Pathologic Basis of Disease. Elsevier Saunders, 8th edition, 2009 Literature Published papers that are referred to during the lectures will be provided through blackboard

Relevant websites www.uptodate.com/contents/search www.ncbi.nlm.nih.gov/pubmed/ www.medicaleducation.nl: TRC Pharmacology Database www.blackboard.leidenuniv.nl

http://www.uptodate.com/contents/search

http://www.ncbi.nlm.nih.gov/pubmed/

http://www.medicaleducation.nl/

http://www.blackboard.leidenuniv.nl/

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Themes

Week 1: Development and Anatomy, Molecular Medicine Week 2: Physiology of Heart and Vessels Week 3: Hemostasis and Thrombosis Week 4: Macrovascular disease 1/2 Week 5: Macrovascular disease 2/2 Week 6: Clinical diagnosis and therapy of macrovascular disease Week 7: Vascular Surgery and Peripheral Artery Disease Week 8: Microvascular disease Week 9: Innovation week, novel therapeutic strategies in CVD Week 10: Case-report

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Week 1 Development and anatomy of the cardiovascular system, molecular medicine

Clinical coordinators Atsma Topics LE Lecture Scientific coordinators van Zonneveld, de Bruin Embryology of the cardiovascular system SS Self Study

Genetic variations in cardiovascular development DE Demonstration Other teachers involved Rabelink, van Gils Endothelial cell biology WO Workgroup

van der Veer Mechanisms in vascular maintenance and repair PR Practical workDe Ruiter, de Boer, van Wisse, van Munsteren

The basics of molecular cell biology and gene expression DB Debate

Bijkerk The technique of PCRvan Vlijmen Animal models in vascular biology

Monday Opening of the Academic Year01-Sep

Tuesday The vascular endothelium02-Sep

9.00-9.45 LE Introduction by the block coördinators

The outline of the minor will be presented: what you can expect, what is expected of you, and what do you expect to learn.

V4-50 van Zonneveld, Atsma, de Bruin

9.45-10.00 Break

10.00-10.45 LE The vascular endothelium In this lecture you will learn that the vascular endothelium is more then just a structural barrier between the vascular wall and blood

V4-50 van Zonneveld

10.45-11.00 Break11.00-12.00 LE The glycocalyx The essential luminal layer V4-50 Rabelink12.00-13.30 Lunch13.30-15.30 SS Molecular biology Study material related to the coming molecular biology class and PCR

workshopV4-46 van der Veer, de Bruin

Wednesday Vasculogenesis03-Sep

9.00-9.45 LE The start of the heart In this hour, you will learn about the stages of embryonal development of the human heart

V4-62 de Ruiter

9.45-10.00 Break10.00-10.45 LE The origin and differentiation

of the vasculatureIn this hour, you will learn about the stages of embryonic development of the vascular system

V4-62 de Ruiter

10.45-11.00 Lunch11.00-12.00 LE Vascular regeneration The role of endothelial progenitor cells in vascular maintenance and repair V4-62 de Boer12.00-13.30 Lunch13.30-15.30 PR Development mouse

embryoDigital microscopy of cardiovascular development in the mouse embryo. BRING LAPTOP

V4-18/22 DeRuiter, van Wisse, van Munsteren

Thursday Introduction to molecular medicine04-Sep

9.00-9.45 LE From DNA to protein 1/2 This lecture will give an overview of the central dogma in molecular cell biology. Gene transcription and translation will be discussed.

V4-62 van der Veer

9.45-10.00 Break10.00-10.45 LE Novel concepts in Post-

transcriptional regulationComplex organisms have only developed flowing the introduction of post-transcrptonal regulation. Defects in post-transcriptional regulation cause disease and offers novel therapeutic targets

V4-62 van der Veer

10.45-11.00 Break11.00-12.00 PR Introduction to PCR An introduction to the technique of PCR will be given, that you will perform

yourself this afternoonV4-62 de Bruin, Bijkerk

12.00-13.30 Lunch13.30-15.30 PR Hands on molecular cell

biology 1/2A tour through a molecular cell biology laboratory will be hosted by researchers and you will perform a PCR experiment to determine gene expression in

D2-19 de Bruin, Bijkerk

Friday Molecular medicine05-Sep

9.00-10.30 PR Hands on molecular cell biology 2/2

The PCR performed on Tuesday will be finished and evaluated V2-34 de Bruin, Bijkerk

10.30-10.45 Break11.00-12.00 LE Transgenic mouse models

in cardiovascular diseasesiRNA and conditional knock-out models are increasingly important in experimental animal models here you will learn their principles

V2-34 van Vlijmen

12.00-13.00 Lunch13.00-13.45 LE microRNAs in vascular

homeostasisAn illustration of how microRNA-126 is a critical regulator of vascular regeneration

V2-34 Bijkerk

13.45- 17.00 SS time to work on your blog home/library

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Week 1: Development and anatomy of the cardiovascular system, molecular medicine Coordinator(s): van Zonneveld, Atsma Teachers: Rabelink, van der Veer, de Bruin, de Ruiter, van Wisse, van Munsteren, van Vlijmen, Bijkerk Outline Next to a detailed introduction into the goals and format of the half minor, this week will be devoted to review the development and anatomy of the cardiovascular system focusing on the heart and blood vessels. Also students will be introduced into how genetic variation can impact on cardiovascular development and lead to defects in mice and man. We will review the central role of the endothelium in vascular homeostasis and discuss how endothelial integrity is maintained in post-natal life. Also, to provide the basic knowledge needed to understand the molecular-medicine based novel therapeutic approaches that will be discussed throughout the course, lectures and a practical assignment will be devoted to review current concepts in molecular biology. In particular, this effort aims to help the students understand novel RNA-based regulatory mechanism that are increasingly recognized to be involved in pathogenesis of human disease and are currently demonstrated to provide potent therapeutic tools. Topics

• Embryology of the cardiovascular system • Genetic variations in cardiovascular development • The biology of the endothelium • Mechanisms in vascular maintenance and repair • The basics in current molecular cell biology and gene expression • The technique of PCR • Animal models in vascular biology

Evaluation

• Evaluation of blog contribution • Multiple choice exam week 3 • Evaluation of paper presentation

Day to Day program Monday 1 September Free: Opening of the academic year Tuesday 2 September Theme: The vascular endothelium 9.00-9.45 Introduction Title Introduction to the half minor by the block coordinators Instructors D.E Atsma (Cardiology), A.J. van Zonneveld (Nephrology) Description The outline of the course will be presented: what you can expect, what is expected of you and

what can you expect to learn 10.00-10.45 Lecture Title The vascular endothelium Instructor A.J. van Zonneveld (Nephrology) Description The vascular endothelium is more than a structural barrier between the vascular wall and the

bloodstream. It serves to regulate vascular tone, permeability, leukocyte migration and vascular homeostasis. The basics of these processes will be discussed.

Literature Basic: Kumar, Abbas en Fausto and Clark Chapter 11 “Blood vessels” part 1”vascular wall cells and their response to injury”.

Preparation Additional reading: Endothelial function and dysfunction, Deanfield et al. Circulation, 2007 (115) 1285-1295

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11.00-12.00 Lecture Title The glycocalyx Instructors T.J. Rabelink (Nephrology) Description The endothelial surface layer (ESL) is a negatively charged carbohydrate rich layer on the

luminal side of the endothelium and is present throughout the whole vasculature. The ESL is located in between the circulating blood and the endothelium with its underlying tissues which supports the hypothesis that the ESL has a vital role in the vasculature. The surface layer has been proposed to be the first barrier for circulating components and protects the endothelium from direct contact with leukocytes and platelets. Consequently it is also suggested to be the first target for damaging agents present within in the vasculature and therefore potentially an interesting candidate as early endothelial damager marker. It has been demonstrated that the ESL is involved in mechano-sensing of the flowing blood, contributes to the endothelial permeability properties and has a protective function against inflammation and coagulation. Therefore, it can be reasoned that the ESL plays an important role in endothelial function and vascular stability. Perturbation of these functions have been implicated in the development of cardiovascular disease (CVD) and kidney disease. This pathophysiology of the ESL and its possible implications for clinical medicine will be discussed in the lecture

13.30-15.30 Self-study Title Molecular Biology and PCR workshop Instructors E.P. van der Veer, R. de Bruin Nephrology) Description Study material related to the coming molecular biology class and PCR workshop Wednesday 3 September Theme: Vasculogenesis 9.00-9.45 Lecture Title The start of the heart Instructor M.C. de Ruiter (Anatomy and Embryology) Description The embryonic heart develops from the splanchnic mesoderm in close relationship with the

developing gut. It starts with a 2D network of endothelial precursors covered by a layer of myocardial cells which remodels into a 3D heart tube. This heart tube is the first functional organ in the embryo. This primary heart tube with an common venous inlet and an arterial outlet has to be septated to obtain a four chambered heart with valves. Both intrinsic cardiac remodelling processes and extracardiac cellular contributions are major key players for proper cardiac septation. Multiple signalling pathways have to be framed in exact spatiotemporal windows during development. A small deviation in one of these processes can easily affect cellular differentiation or contribution and harm normal development resulting in dramatic congenital cardiac malformations and even embryonic lethality. We will discuss the consequences of disturbed developmental processes with the help of major cardiac malformations.

10.00-10.45 Lecture Title The origin and differentiation of the vasculature Instructor M.C. de Ruiter (Anatomy and Embryology) Description All blood vessels in the develop from a small endothelial tube within an undifferentiated

mesenchyme. The interaction between these two cell populations in combination with an increasing blood flow determines the ultimate composition of the vessel wall. Various embryonic cell populations (e.g. neural crest, epicardium, second heart field, endothelium) contribute to the smooth muscle and fibroblasts compartments of the vessel wall. These contributions are strictly regulated processes and have sharp topographic boundaries. A change in cellular contribution coincides in a change in morphology, basic cellular signalling processes and function. Moreover most of the cells contributing to the vessel wall also contribute to the developing heart which explains that many congenital cardiac malformations are associated with vascular malformations like abnormal venous or arterial patterning and/or composition

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11.00-11.45 Lecture Title Vascular regeneration Instructors H.C. de Boer (Nephrology) Description Endothelial progenitor cells contribute to the maintenance of the vascular system.

You will get insight into the definition and origin of endothelial progenitor cells and the consequences of exhaustion of these cells.

Literature Basic: “Regeneration of the vascular compartment”. Authors: Becher, Nickenig and Werner. Herz, 2010 (35):342-351.

Preparation Additional reading: “Restoring the renal microvasculature to treat chronic kidney disease”. Authors: Long, Norman and Fine. Nature Review Nephrology, 2012 (8): 244-250.

13.30-15.30 Practicum Title Digital microscopy of cardiovascular development in the mouse embryo Instructor M.C. deRuiter, B.Wisse, C. van Munsteren (Anatomy and Embryology) Description Developmental biologists frequently use transgenic and knock out mouse models to study the

role of specific molecular signalling pathways. In this practical lesson you will be introduced in one of the research methods to study normal and abnormal cardiovascular development. First a series of transverse sections of a normal 15 days old mouse embryo will be studied. You will focus on the various cell populations within the cardiac outflow tract and the great arteries (aorta and pulmonary arteries). After you have proven to be able to recognize all essential structures in the thorax you will be challenged to determine the cardiovascular malformations in one or more knock out models (e.g. VEGF, PDGF, LRP2 knock out mice). In a general discussion you will present your findings to the other students and relate the abnormalities with the known developmental processes.

Thursday 4 September Theme: Current concepts in molecular biology 9.00-9.45 Lecture Title From DNA to protein 1/2 Instructor E.P. van der Veer (Nephrology) Description The central dogma of cellular biology proposed by Francis Crick in the 1950’s details a

process whereby DNA in the nucleus is transcribed into RNA, which is subsequently translated into protein in the cytoplasm. It is now clear that this chronological view of DNA to protein is a simplification. This lecture will provide insight into the molecular mechanisms by which encrypted genomic information in the DNA leads to functional elements (RNA and protein) that drive multitudes of cellular functions.

Literature Manel Esteller. Non-coding RNAs in human disease. Nature Reviews Genetics, 12, 861-874, 2011.

10.00-10.45 Lecture Title Novel concepts in post-transcriptional regulation Instructor E.P. van der Veer (Nephrology) Description The broad-scale introduction of post-transcriptional regulatory mechanisms is what defines

complex organisms (eukaryotes) as compared to their more primitive counterparts (prokaryotes and eubacteria). This lecture is designed to introduce the wide arsenal of tools the cell employs to modulate gene expression at the RNA level, influencing the stability and localization of targets. Light will also be shed on how defects in post-transcriptional regulation can be causal for various diseases and how targeting RNA is considered to be a new frontier in the treatment of disease.

Literature Esteller, M. Non-coding RNAs in human disease. Nature Reviews Genetics, 12, 861-874, 2011.

Kafasla, P, et.al. Post-transcriptional coordination of immunological responses by RNA-binding proteins. Nature Immunology, 15(6), 492-502, 2014.

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11.00-12.00 Practicum Title Introduction to PCR Instructor R. de Bruin, R. Bijkerk (Nephrology) Description An introduction to the technique of PCR will be given, that you will perform yourself this

afternoon 13.30-15.30 Practicum I Title Hands-on molecular biology Instructor R. de Bruin, R. Bijkerk (Nephrology) Description A tour through a molecular cell biology laboratory will be hosted by researchers and you will

perform a PCR experiment to determine gene expression in endothelial cells and smooth muscle cells. Half of the students will perform qRT-PCR, the other qPCR and electrophoresis.

Friday 5 September Theme: Molecular Medicine 9.00-10.30 Practicum II Title Hands-on molecular biology Instructor R. de Bruin, R. Bijkerk (Nephrology) Description The PCR performed on Tuesday will be finished and evaluated. 11.00-12.00 Lecture Title Transgenic mouse models in cardiovascular disease Instructor B.J.M. van Vlijmen Description The mouse has been used as an experimental model for cardiovascular research for a only a

short time; however, the sophisticated genetics of this species has resulted in a number of innovative approaches that are not possible with other models. The availability of inbred and mutant strains has resulted in the discovery of a number of genes affecting cardiovascular disease. More importantly, the newer genetic technologies such as transgenic mice and gene-targeted mice are producing important insights into cardiovascular disease. This lecture focuses on murine models of cardiovascular disease and will briefly discuss the several technologies that are now available to generate such models (transgenesis, (conditional) knockout, CRISPR, and RNA interference). We will summarize a number of mouse models of hyperlipidemia, atherosclerosis and thrombosis and discuss the contribution of these models to development of novel therapies.

13.00-13.45 Lecture Title MicroRNAS in vascular homeostasis Instructor R. Bijkerk (Nephrology) Description The role of microRNAs in maintaining healthy blood vessels. This is illustrated by microRNA-

126, that acts as a critical regulator of vascular regeneration Literature Hematopoietic MicroRNA-126 Protects against Renal Ischemia/Reperfusion Injury by

Promoting Vascular Integrity. J Am Soc Nephrol, 2014. Preparation Additional reading: Pervasive roles of microRNAs in cardiovascular biology. Small & Olson.

Nature, 2011.

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Week 2 Physiology of heart and vessels

Clinical coordinators Atsma Topics LE Lecture Scientific coordinators Pijnappels Heart function SS Self Study

Electrophysiology 1 and 2 DE Demonstration Other teachers involved Steendijk, de Vries Blood pressure regulation WO Workgroup

Ypey, Trines, Feola, Molecular medicine PR Practical workJangsangthong, Rotmans, DB DebateMajumder, Askar, PhD studs

Monday Heart function08-Sep9.00-9.45 LE Introduction by week coordinators and hand out of case descriptions V4-50 Atsma, Pijnappels

9.45-10.00 Break10.00-10.45 LE Cardiac function V4-50 Steendijk10.45-11.00 Break11.00-12.00 LE Cardiac function - coronary circulation V4-50 ?

12.00-13.30 Lunch13.30-15.30 SS A state-of-the-art scientific

paperState of the art scientific papers will be handed out and sub-groups will be formed. Use this time to prepare short presentations (max 15 minutes)

V4-50

Tuesday Electrophysiology 109-Sep9.00-9.45 LE Electrophysiology of the heart V4-50 Pijnappels

9.45-10.00 Break10.00-10.45 LE Electrical function and ECG V4-50 Ypey10.45-11.00 Break11.00-12.00 LE Supraventricular arrhythmias V4-50 Trines

12.00-13.30 Lunch13.30-15.30 LE/DE Experimental techniques (Patch-clamp and Optical mapping) V4-50 Feola/Jangsangthong

Wednesday Blood pressure regulation10-Sep

10.00-10.45 LE Mechanisms in blood pressure regulation V4-50 Rotmans10.45-11.00 Break11.00-12.00 LE Cardiovascular complications of hypertension V4-50 Rotmans12.00-13.30 Lunch13.30-15.30 WO Paper discussion session This time feedback will be given on the presentations by dr. van de Veer to help

set the standard for the coming weeksV4-50 Pijnappels

Thursday Electrophysiolog 211-Sep

9.00-9.45 LE In silico models of cardiac arrhythmias V4-62 Majumder9.45-10.00 Break

10.00-10.45 LE In vitro models of cardiac arrhythmias V4-62 Askar

10.45-11.00 Break11.00-12.00 LE PhD student projects V4-62 PhD students (3)12.00-13.30 Lunch13.30-14.30 DE/PR Lab visit (Exp. Cardiology, D4) V4-62 Lab members


10.00-11.00 LE Experimental approaches in hypertension V4-50 Rotmans11.00-11.05 Break11.05-12.00 LE Gene therapy for cardiac diseases: Background V4-50 de Vries

12.00-13.30 Lunch13.30-14.30 LE Gene therapy for cardiac diseases: (Pre)clinical application V4-50 de Vries

14.30- 17.00 SS Writing a (short) blog Use this time to work on your blog and case report home/library

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Week 2: Physiology of The Heart and Blood Vessels Coordinator(s): Atsma, Pijnappels Teachers: Steendijk, de Vries, Pijnappels Ypey, Trines, Feola, Jangsangthong, Rotmans, Majumder,

Askar, PhD students Outline This week will begin with handing out the case-descriptions that will serve as the background for the weekly personal blogs and the final case report that will be submitted in the final week of the course. The theme of week two involves key features of the physiology of the cardiovascular system including the mechanical and electrical function of the heart. The electrical conduction system will be demonstrated in particular, as many of the diseases that are discussed in this half minor are the result of congenital or acquired anomalies in these areas. Also, the (advanced) therapies that are discussed target these processes. Deviations in cardiac physiology resulting from (genetic) disease will be discussed. The basic mechanisms underlying the occurrence of arrhythmias and their clinical presentation are outlined. Also we will outline the physiology of blood pressure regulation and talk about the epidemiology, current and novel treatment options, as well as complications of hypertension. The students will be introduced to the basic disease models that are employed in the lab to further investigate the basic underlying disease mechanisms, and novel insights and hypotheses will be discussed. To stimulate self-study, state of the art papers on a topic that relate to the theme of the week will be distributed to the students (groups of 4) with the assignment to prepare a presentation that discusses content, strength and weaknesses of the studies. At the end of the week, the students will update their blogs describing which pathophysiological concepts that were discussed are relevant to their selected patient case. Topics

• Heart function • Electrophysiology of the heart • Arrhythmias • Regulation of blood pressure and hypertension

Evaluation • Evaluation of blog contribution • Multiple choice exam week 3

Day to Day program Monday 8 September Theme: Heart Function 9.00-9.45 Introduction Title Introduction by week coordinators and hand out of case descriptions Instructor D.E. Atsma, D.A. Pijnappels Description Instruction on the role of the case descriptions and how to use them when writing the weekly

blogs. Week by week these blogs will cumulate into a useful document that can form the basis for the case reports. Also the coordinators will outline the theme of the week.

10.00-10.45 Lecture Title Cardiac function Instructor P. Steendijk Description General principles and mechanisms of cardiac physiology are outlined. Literature Boron and Boulpaep, Medical Physiology (2nd ed.), chapters 9, 22 and 25. Preparation Reading literature 11.00-11.45 Lecture Title Cardiac function – Coronary circulation Instructor P. Steendijk Description The role of coronary of circulation in normal cardiac physiology is discussed, as well as

coronary dysfunction in heart disease.

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Literature Boron and Boulpaep, Medical Physiology (2nd ed.), chapter 24 – p581-583. Preparation Reading literature 13.30-15.30 Self-study Title State-of-the-art scientific paper Instructor D.A. Pijnappels Description State of the art scientific papers will be handed out and sub-groups will be formed. Use this

time to prepare a short presentation for Wednesday (max 15 minutes)

Tuesday 9 September Theme: Electrophysiology 1 9.00-9.45 Lecture Title Electrophysiology of the heart Instructor D.A. Pijnappels Description The heart is an organ that generates and propagates electrical signals in a highly organized

manner, thereby favouring optimal pump function. However, disturbances in these electrical processes may contribute to heart rhythm disturbances, which can be lethal. A good mechanistic understanding in these disorders is essential for effective treatment, but also for the development of new therapeutics.

Literature Boron and Boulpaep, Medical Physiology (2nd ed.), chapter 21 Preparation Reading literature 10.00-10.45 Lecture Title Electrical function and ECG Instructors D.L. Ypey Description As the origin of cardiac electrical function lays excitability, the property of a cell to generate

an action potential by subsequent in and effluxes of ions, and propagation, the property of a tissue to conduct an electrical current by means of excitation and coupling. Although occurring in the heart, these processes can be detected and recorded outside the body, thereby producing an electrocardiogram (ECG).

Literature Boron and Boulpaep, Medical Physiology (2nd ed.), chapter 21 Preparation Reading literature 11.00-12.00 Lecture Title Narrow complex tachyarrhythmias Instructors S.A.I.P. Trines Description Heart rhythm disturbances could affect the atria, ventricles or both. Those that involve the

atria, including the atrioventricular node, are refered to as narrow complex tachyarrhythmias. ECG analyses are often used to identify the origin and nature of such arrhythmias.

Literature Uptodate.com: “Clinical manifestations, diagnosis, and evaluation of narrow QRS complex tachycardias”

Preparation Reading literature 13.30-15.30 Lecture (Demonstration) Title Experimental techniques (patch-clamp and optical mapping) Instructors W. Jangsangthong and I. Feola Description Whole-cell patch-clamp is one of the most definite techniques in basic electrophysiology

research. A small glass electrode and a sophisticated microscopy/electrophysiological setup are used to measure and record electrical activity in single cells and tissues. The optical mapping technique makes use of voltage- or calcium-sensitive probes, light-sensitive camera’s and a dedicated microscopy setup.

Literature Physiological Research (Karmazinova et al. 2010. Suppl 1:S1-7) and Circulation Research (Herron et al. 2012. 110(4); 609-623)

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Wednesday 10 September Theme: Blood pressure regulation 10.00-10.45 Lecture Title Mechanisms in blood pressure regulation Instructor J.I. Rotmans (Nephrology) Description Mechanisms of blood pressure regulation will be discussed as well as pathophysiological

mechanisms of hypertension Literature Basic: Kumar and Clark Chapter 12, p597-599 (eighth edition)

Additional: T.M. Coffman. Under pressure: the search for the essential mechanisms of hypertension. Nature Medicine 2011; Nov 7;17(11):1402-9

Preparation Reading literature 11.00-12.00 Lecture Title Cardiovascular complications of hypertension Instructor J.I. Rotmans (Nephrology) Description Complications and treatment options for hypertension will be discussed. Literature Basic: Kumar and Clark Chapter 14, p777-784 (eighth edition) Additional literature:

1. A. Myat. Resistant hypertension. BMJ 2012;345:e7473 2. Lewington S et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002 Dec 14;360(9349):1903-13

Preparation reading literature 13.30-15.30 Workgroup Title Paper presentation and Discussion session 1 Instructor D.A. Pijnappels and E.P van der Veer Preparation Powerpoint presentation (15 min)

Thursday 11 September Theme: Electrophysiology 2 9.00-9.45 Lecture Title In silico models of cardiac arrhythmias Instructor R. Majumder Description The degree of complexity of certain biological/electrophysiological processes becomes so high

that a human brain can no longer comprehend these processes. One way to deal with such processes is to develop realistic computer models that are based on numerical reasoning. Studies on the underlying mechanisms of cardiac arrhythmias have benefited a lot from such so-called in silico studies as new therapeutic were proposed, which indeed turned out to be of significant biological and therapeutic relevance.

Literature Am J Phyiol Heart Circ Physiol (Roberts et al. 2012. 303(7); H766-H783. Preparation Reading literature 10.00-10.45 Lecture Title In vitro models of cardiac arrhythmias Instructor S.F.A. Askar Description The heart is an extremely complex 3D organ that is both electrically and mechanically active.

Mechanistic studies on the origin and termination of cardiac arrhythmias are hampered by the 3D nature of cardiac tissue as the interpretation of data is seriously affected. One way to reduce this complexity is to culture the cardiac cells of interest in confluent monolayers (no a-cellular space), allowing standardized and controllable studies on the underlying mechanisms of rhythm disorders. Such an approach certainly becomes with trade-offs, but studies have shown that key features of cardiac arrhythmias can be studied in such monolayers and have resulted in important novel insights.

Literature Cardiovasc Res (Askar et al. 2013. 97(1); 171-181. Preparation Reading literature

http://www.ncbi.nlm.nih.gov/pubmed?term=Lewington%20S%5BAuthor%5D&cauthor=true&cauthor_uid=12493255

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11.00-12.00 Lecture Title PhD student projects Instructor 3 PhD students Description You might want to pursue a PhD training upon finishing your Master/Medical studies. During

this lecture, 3 PhD students from the Department of Cardiology will present their recent work and share some of their experiences with you.

13.30-14.30 Demonstration/practical work Title Lab visit (Exp. Cardiology, D4) Instructor Lab members Description The laboratory of Experimental Cardiology is part of the Department of Cardiology and

accommodates scientists of various kinds. They will show you the various experimental setups and models that are used to study cardiac disease and to identify novel therapeutic targets.

Friday 12 September Theme: Molecular Medicine 10.00-11.00 Lecture Title Experimental approaches in hypertension Instructor J.I Rotmans Description New therapeutic strategies to control hypertension will be discussed. Literature 1. S. Laurent. New drugs, procedures, and devices for hypertension. Lancet 2012; 380: 591–

600 2. D.L. Bhatt. A controlled trial of renal denervation for resistant hypertension. NEJM 2014;

370;393-401 Preparation Reading literature 11.05-12.00 Lecture Title Gene therapy for cardiac diseases: Background Instructor A.A.F. de Vries Description The rationales behind gene therapy will be discussed, as well as the methods and techniques

used to accomplish the aims of gene therapy. Literature Vannucci L, Lai M, Chiuppesi F, Ceccherini-Nelli L, Pistello M. Viral vectors: a look back

and ahead on gene transfer technology. New Microbiol 2013;36:1-2 Preparation Reading literature 13.30-14.30 Lecture Title Gene therapy for cardiac diseases: (Pre)clinical application Instructor A.A.F. de Vries Description Various cardiac diseases have been target by gene therapy using viral vectors. Although most

of these studies were performed in pre-clinical stages, a growing number of clinical studies have been published with promising results.

Literature Publication in Circulation Research (Zacchigna et al. 2014. 114:1827-1846) Preparation Reading literature 14.30-17.00 Self-study Title Blog update Instructor Assigned mentor Description Use this time to work on your blog and case report

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Week 3 Thrombosis and Hemostasis

Clinical coordinators Eikenboom, Huisman Topics LE Lecture Scientific coordinators Reitsma Coagulation and fibrinolysis SS Self Study

Venous thrombosis DE Demonstration Other teachers involved van der Meer Anticoagulant therapy WO Workgroup

van Vlijmen Hemophilia and clinical management PR Practical workBos, Huisman Acute coagulation disorders DB DebateKlok, Versteeg

Monday Pathophysiology of Blood Coagulation15-sep

09.00-09.45 LE Primary hemostasis and its disorders V4-18/22 Eikenboom09.45-10.00 Break10.00-10.45 LE Secondary hemostasis and fibrinolysis V4-18/22 Versteeg10.45-11.00 Break11.00-11.45 LE Disorders of secondary hemostasis; bleeding and thrombosis V4-18/22 Van Vlijmen11.45-13.30 Lunch13.30-15.30 SS Assignments and preparation patient demonstrations V3-36 Eikenboom

Tuesday Clinical and laboratory diagnostics16-sep

09.00-09.45 PD Patient with venous thromboembolism V3-18/22 Huisman09.45-10.00 Break10.00-10.45 LE Imaging diagnostics in thrombosis and clinical decision rules V3-18/22 Huisman10.45-11.00 Break11.00-12.00 LE Laboratory diagnosis of coagulation disorders V3-18/22 Bos/Eikenboom12.00-13.30 Lunch13.30-15.30 WO Interactive case presentations V2-10/14 Klok/Eikenboom

Wednesday Treatment of coagulation disorders17-sep

09.00-09.45 PD Patient with (inherited) bleeding disorder V4-50 Van der Meer09.45-10.00 Break10.00-10.45 LE Prohemostatics V4-50 Van der Meer10.45-11.00 Break11.00-12.00 LE Anticoagulants and profibrinolytic treatment V4-50 Huisman12.00-13.30 Lunch13.30-15.30 WO Interactive case presentations V4-46 van der Meer/Klok

Thursday Acute derangement of hemostasis and new biologicals18-sep

09.00-10.30 LE TTP, aHUS and HIT V2-10/14 Eikenboom10.30-10.45 Break10.45-12.15 LE Novel anticoagulant- and hemostatic biologicals V2-10/14 Bos/Reitsma12.15-13.00 Lunch13.00- 17.00 SS Writing a (short) blog Use this time to work on your blog

Friday Exam19-sep

11.00-12.00 EX Knowledge test 1 Covering week 1-3 V2-34

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Week 3: Thrombosis and Hemostasis Coordinator(s): Eikenboom, Huisman, Reitsma Teachers: Van der Meer, Huisman, Klok, van Vlijmen, Bos, Versteeg Outline: The week will begin with an in-depth instruction of the workings of the hemostatic and fibrinolytic systems with the goal to give the student a detailed working knowledge of blood coagulation and fibrinolysis. The second day will start with a patient demonstration in which a case with venous thrombosis is presented. This is followed by lectures that deal with diagnostics, with an emphasis on imaging techniques, laboratory analyses, and clinical decision rules. The afternoon session will follow an interactive case presentation format, which will allow the student to learn how to correctly apply the diagnostic tools in a clinical setting. The third day will follow a similar format, but the patient demonstration will focus on a patient with a bleeding disorder and the subsequent lectures and interactive cases will be focussed on treatment of coagulation disorders. The fourth day will be devoted to acute severe derangements of the coagulation system such as heparin-induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), and atypical hemolytic uremic syndrome (aHUS). In addition the latest developments in the innovation of treatment for thrombotic and bleeding disorders will be presented. In the afternoon there will be time to work on the Blog that is part of the requirements of the minor. Topics:

• Coagulation and fibrinolysis • Venous thrombosis • Anticoagulant therapy • Hemophilia and clinical management • Acute coagulation disorders

Evaluation

• Evaluation of blog contribution • Multiple choice exam week 3 • Evaluation of participation in the interactive case presentations

Day to Day program Monday, September 15 Theme: Pathophysiology of Blood Coagulation 09.00-9.45 Lecture Title Primary hemostasis and its disorders Instructor H.C.J. Eikenboom (Thrombosis and Hemostasis) Description This lecture will introduce the hemostatic system with emphasis on primary hemostasis and its

most common disorders. Literature Relevant sections from the following books and journal article:

Robins and Cotran, Pathologic basis of disease, 8th edition 2010; chapter 4, pages 115-133 and chapter 14, pages 666-674 Kumar and Clark, Clinical Medicine, 8th edition 2012; chapter 8, pages 414-429 McPhee, Pathophysiology of disease, 6th edition 2010; chapter 6, pages 111-122, 131-137 New fundamentals in hemostasis. Henri H. Versteeg et al. Physiol Rev 2013;93: 327–358

Preparation Reading of the literature 10.00-10.45 Lecture Title Secondary hemostasis and fibrinolysis Instructor H.H. Versteeg (Thrombosis and Hemostasis) Description This lecture will expand on the lecture on primary hemostasis and discuss secondary

hemostasis and fibrinolysis Literature Relevant sections from the following books and journal article:

Robins and Cotran, Pathologic basis of disease, 8th edition 2010; chapter 4, pages 115-133 and

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chapter 14, pages 666-674 Kumar and Clark, Clinical Medicine, 8th edition 2012; chapter 8, pages 414-429 McPhee, Pathophysiology of disease, 6th edition 2010; chapter 6, pages 111-122, 131-137 New fundamentals in hemostasis. Henri H. Versteeg et al. Physiol Rev 2013;93: 327–358

Preparation Reading the literature 11.00-11.45 Lecture Title Disorders of secondary hemostasis; bleeding and thrombosis Instructor B.J.M. van Vlijmen (Thrombosis and Hemostasis) Description This lecture will expand on the introduction to secondary hemostasis and teach the most

common disorders of secondary hemostasis Literature Relevant sections from the following books and journal article:


Preparation Reading the literature 13.30-15.30 Self-study Title Assignments and preparation patient demonstrations Instructor Not applicable Description On the first day of the course the self-study assignments for the preparation of the patient

demonstrations will be given. Literature To be announced Preparation NA Tuesday, September 16 Theme: Clinical and laboratory diagnostics 09.00-9.45 Patient demonstration Title Patient with venous thombosis Instructor M.V. Huisman (Thrombosis and Hemostasis) Description A patient with venous thrombosis will be presented and clinical details will be discussed. The

students will have an opportunity to ask questions. Literature Relevant sections from the following books and journal article:


Preparation Reading the literature. Completing the self-study assignments of Monday 10.00-10.45 Lecture Title Imaging diagnostics in thrombosis and clinical decision rules Instructors M.V. Huisman (Thrombosis and Hemostasis) Description The imaging options that are available for the diagnosis of venous thrombosis will be

presented, and also the laboratory investigations. Clinical decision rules that are commonly used will also be presented.

Literature Relevant sections from the following books and journal article: Robins and Cotran, Pathologic basis of disease, 8th edition 2010; chapter 4, pages 115-133 and chapter 14, pages 666-674 Kumar and Clark, Clinical Medicine, 8th edition 2012; chapter 8, pages 414-429 McPhee, Pathophysiology of disease, 6th edition 2010; chapter 6, pages 111-122, 131-137 New fundamentals in hemostasis. Henri H. Versteeg et al. Physiol Rev 2013;93: 327–358

Preparation Reading the literature. Completing the self-study assignments of Monday. 11.00-12.00 Lecture Title Laboratory diagnosis of coagulation disorders Instructors M.A. Bos/H.C.J. Eikenboom (Thrombosis and Hemostasis)

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Description Routine and specialized laboratory investigations are a crucial part of the diagnostic work-up of patients with a prominent bleeding or thrombotic tendency. The nature of these investigations and when to order which coagulation test will be presented.

Literature Relevant sections from the following books and journal article: Robins and Cotran, Pathologic basis of disease, 8th edition 2010; chapter 4, pages 115-133 and chapter 14, pages 666-674 Kumar and Clark, Clinical Medicine, 8th edition 2012; chapter 8, pages 414-429 McPhee, Pathophysiology of disease, 6th edition 2010; chapter 6, pages 111-122, 131-137 New fundamentals in hemostasis. Henri H. Versteeg et al. Physiol Rev 2013;93: 327–358

Preparation Reading the literature 13.30-15.30 Workgroup Title Interactive case presentations Instructors F.A. Klok/H.C.J. Eikenboom (Thrombosis and Hemostasis) Description Clinical cases focused on the diagnostic approaches in patients with thrombosis or bleeding

disorders will be handed out and discussed in detail with the students. Active participation of all students is expected and performance will be judged.

Literature NA Wednesday, September 17 Theme: Treatment of coagulation disorders 09.00-9.45 Patient demonstration Title Patient with (inherited) bleeding disorder Instructor F.J.M. van der Meer (Thrombosis and Hemostasis) Description A patient with a bleeding disorder will be presented and clinical details will be discussed. The

students will have an opportunity to ask questions Literature Relevant sections from the following books and journal article: Robins and Cotran, Pathologic basis of disease, 8th edition 2010; chapter 4, pages 115-133 and

chapter 14, pages 666-674 Kumar and Clark, Clinical Medicine, 8th edition 2012; chapter 8, pages 414-429 McPhee, Pathophysiology of disease, 6th edition 2010; chapter 6, pages 111-122, 131-137 New fundamentals in hemostasis. Henri H. Versteeg et al. Physiol Rev 2013;93: 327–358 Preparation Reading the literature 10.00-10.45 Lecture Title Prohemostatics Instructor F.J.M. van der Meer (Thrombosis and Hemostasis) Description The treatment options for inherited and acquired bleeding disorders will be discussed Literature Relevant sections from the following books and journal article: Robins and Cotran, Pathologic basis of disease, 8th edition 2010; chapter 4, pages 115-133 and

chapter 14, pages 666-674 Kumar and Clark, Clinical Medicine, 8th edition 2012; chapter 8, pages 414-429 McPhee, Pathophysiology of disease, 6th edition 2010; chapter 6, pages 111-122, 131-137 New fundamentals in hemostasis. Henri H. Versteeg et al. Physiol Rev 2013;93: 327–358 Preparation Reading the literature 11.00-12.00 Lecture Title Anticoagulants and profibrinolytic treatment Instructor M.V. Huisman (Thrombosis and Hemostasis) Description Treatment but also prevention of venous thrombosis will be discussed. Emphasis will be on

current and new oral anticoagulants, but other treatment option will also be presented Literature Relevant sections from the following books and journal article: Robins and Cotran, Pathologic basis of disease, 8th edition 2010; chapter 4, pages 115-133 and

chapter 14, pages 666-674 Kumar and Clark, Clinical Medicine, 8th edition 2012; chapter 8, pages 414-429 McPhee, Pathophysiology of disease, 6th edition 2010; chapter 6, pages 111-122, 131-137 New fundamentals in hemostasis. Henri H. Versteeg et al. Physiol Rev 2013;93: 327–358 Preparation Reading the literature

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13.30-15.30 Workgroup Title Interactive case presentations Instructors F.J.M. van der Meer/F.A. Klok (Thrombosis and Hemostasis) Description Clinical cases focussed on the treatment options in patients with thrombosis or bleeding

disorders will be handed out and discussed in detail with the students. Active participation of all students is expected and performance will be judged.

Literature NA Thursday, September 18 Theme: Acute derangement of hemostasis and new biologicals 09.00-10:30 Lecture Title TTP, aHUS and HIT Instructor H.C.J. Eikenboom (Thrombosis and Hemostasis) Description Some patients will experience acute and very severe derangements of the hemostatic system.

The clinical presentation of these severe disorders and the laboratory diagnosis will be presented

Literature Relevant sections from the following books and journal article: Robins and Cotran, Pathologic basis of disease, 8th edition 2010; chapter 4, pages 115-133 and

chapter 14, pages 666-674 Kumar and Clark, Clinical Medicine, 8th edition 2012; chapter 8, pages 414-429 McPhee, Pathophysiology of disease, 6th edition 2010; chapter 6, pages 111-122, 131-137 New fundamentals in hemostasis. Henri H. Versteeg et al. Physiol Rev 2013;93: 327–358 Preparation Reading the literature 10.45-12.15 Lecture Title Novel anticoagulant- and hemostatic biologicals Instructor M.A. Bos/P.H. Reitsma (Thrombosis and Hemostasis) Description Biologicals have always played an important role in the treatment of patients with thrombotic

and in particular bleeding disorders. There is always room for improvement and the latest scientific developments will be presented.

Literature Not applicable Preparation Not applicable 13.00-17.00 Self-study Title Blog update Instructor Assigned mentor Description Use this time to work on your blog and case report Friday, September 19 Theme: Exam 11.00-12.00 Exam Title Knowledge test 1 Instructor NA Description Covering week 1-3

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Week 4 Macrovascular disease: atherosclerosis 1

Clinical coordinators Pereira LE Lecture Scientific coordinators Rensen, Willems van Dijk SS Self Study

Topics DE Demonstration Other teachers involved Jukema Dyslipidemia etiology, classification, prevention and treatment WO Workgroup

Pijl, Berbee Metabolic syndrome, obesity and type-2 diabetes PR Practical workHuisman Atherosclerosis: etiology, classification and treatment DB DebateWang, Boon Pathogenesis of atherosclerosis: inflammationvan Harmelen Novel insights in metabolism: brain and fatKuiper The microbiome

Monday Dyslipidemia22-Sep

9.00-9.45 LE Introduction by the block coordinators V4-50 Rensen, Pereira9.45-10.00 Break

10.00-10.45 LE Lipid Lipid metabolism and dyslipidemia, etiology and classification V4-50 Rensen10.45-11.00 Break11.00-12.00 LE Clinical management of Clinical management of dyslipidemia: prevention and treatment V4-50 Jukema12.00-13.30 Lunch

13.30-17.00 SS A state of the art scientific paper

Select paper for presentation (approx. 10 preselected) V4-50 Rensen, Willems van Dijk

Tuesday Obesity, Metabolic Syndrome and Type 2 Diabetes23-Sep

9.00-9.45 LE Obesity and Metabolic

Obesity and MetS - etiology V4-50 Willems van Dijk9.45-10.00 Break

10.00-10.45 LE Atherosclerosis T2DM - prevention and treatment V4-50 Pijl10.45-11.00 Break

11.00-12.00 DB Propositions Discussion on topics lipid metabolism, MetS and T2DM V4-50 Rensen/Willems van Dijk12.00-13.30 Lunch

13.30-17.00 WO Paper presentations Understand therapeutic interventions on lipid metabolism V4-50 Rensen

Wednesday Atherosclerosis24-Sep

9.00-9.45 LE Atherosclerosis Human atherosclerosis and experimental models V4-50 Berbée9.45-10.00 Break

10.00-10.45 WO Atherosclerosis Critical parameters for patients at risk V4-50 Huisman10.45-11.00 Break11.00-12.00 DE Patient demonstration Understanding end-points in atherosclerosis V4-50 Huisman12.00-13.30 Lunch

13.30-17.00 PR Vascular pathology Classification of atherosclerosis by histology V4-50 Berbée/Wang\

Thursday Pathogenesis of inflammation25-Sep

9.00-9.45 LE Introduction inflammation,

Role of inflammation in adipose tissue V4-62 Van Harmelen9.45-10.00 Break

10.00-10.45 LE Vascular inflammation Role of inflammation in atherosclerosis V4-62 Kuiper12.00-13.00 Lunch

13.00-17.00 PR Practical relationship

Correlating glucose tolerance with body fat V4-62 Willems van Dijk/Rensen


9.00-9.45 LE Brain Role of brain in lipid and glucose metabolism V4-50 Rensen9.45-10.00 Break

10.00-10.45 LE Brown fat BAT as potential target in MetS V4-50 Boon10.45-11.00 Break11.00-12.00 LE Microbiome Role of gut in MetS V4-50 Willems van Dijk12.00-13.00 Lunch13.00- 17.00 SS Writing a (short) blog Use this time to work on your blog home/library

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Week 4: Macrovascular disease 1 Coordinator(s): Rensen, Willems van Dijk, Pereira Teachers: Willems van Dijk, Huisman, Berbée, Biermasz, Boon, van Harmelen,

Jukema, Kuiper, Wang

Outline In our current society, obesity and the concomitant development of the “Metabolic Syndrome” are reaching epidemic proportions. The metabolic syndrome is defined by the co-occurrence of obesity, dyslipidemia, insulin resistance, hypertension and low grade inflammation. The main objective of this part of the minor is to provide insight in the associations and underlying mechanisms that link these risk factors with the development of type 2 diabetes and especially with macrovascular disease. The basic lectures will discuss the role of specific risk factors in the aetiology of type 2 diabetes and macrovascular disease and also discuss novel avenues for risk prevention, prediction and treatment. Simultaneously, the clinical presentations will be focussed on recognizing and treating patients at risk. Topics

• Dyslipidemia etiology, classification, prevention and treatment • Obesity, metabolic syndrome, and type 2 diabetes • Atherosclerosis: etiology, classification and treatment • Pathogenesis of atherosclerosis: inflammation • Novel insights in metabolism: brain and fat • The microbiome

Evaluation


Day to Day program Monday, September 22 Theme: Dyslipidemia 9.00-9.45 Introduction Title Introduction by the block coordinators Instructors P.C.N. Rensen, A.M. Pereira (Endocrinology) Description This lecture will give an overview of the various topics that will be dealt with in

‘Macrovascular disease’ (weeks 4 and 5). 10.00-10.45 Lecture Title Lipid metabolism and dyslipidemia - etiology and classification Instructor P.C.N. Rensen (Endocrinology) Description Dyslipidemia, characterized by increases triglycerides and LDL-cholesterol, and decreased

HDL-cholesterol, is a crucial risk factor for the development of atherosclerosis. This lecture will provide an overview of the role of lipoproteins in the transport of triglycerides and cholesterol between organs. The mechanism(s) underlying the consequences of disturbed lipoprotein metabolism for the development of atherosclerosis will be explained. In addition, monogenetic causes of dyslipidemia and molecular targets for treatment of dyslipidemia will be briefly discussed.

Literature Text book: • Kumar & Clark, Clinical Medicine, 7th edition, Chapter 19, pages 1061-1063

(disorders of lipid metabolism/lipid physiology) • Robbins and Cotran, Pathologic basis of disease, 8th edition 2010; chapter 8, pages

496-506 (atherosclerosis/consequences of atherosclerotic disease). Selected reviews:

• Diagnosis and treatment of familial hypercholesterolemia. Hoving GK et al. Eur Heart J 2013, 34: 962-71.

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• Antisense oligonucleotides for the treatment of dyslipidemia. Visser ME et al. Eur Heart J 2012, 33: 1451-8.

Preparation Reading of the literature 11.00-12.00 Lecture Title Clinical management of dyslipidemia: prevention and treatment Instructor J.W. Jukema (Cardiology) Description Dyslipidemias may lead to atherosclerosis and its adverse clinical sequelae like myocardial

infarction and cardiac death. The main dyslipidemias are elevated LDL (atherogenenic particle)-cholesterol levels and low HDL (supposed protective particle)-cholesterol levels. The lecture will deal with the latest insight on how to treat these two main dyslipidemias. Focus on further LDL-cholesterol lowering or on HDL-cholesterol elevation?

Literature Text book: • Kumar, Abbas en Fausto and Clark Chapter?

Selected reviews: • Emerging drugs for coronary artery disease: from past achievements and current

needs to clinical promises. Ahmed TA et al. Expert Opin Emerg Drugs 2011, 16: 203-33 (only main messages should be studied).

• Journey through cholesteryl ester transfer protein inhibition: from bench to bedside. Karalis I. et al. Circ Cardiovasc Qual Outcomes 2013, 6, 360-6.

Preparation Reading of the literature 13.30-17.00 Self-study Title State of the art scientific paper session II Instructor P.C.N. Rensen (Endocrinology), K. Willems van Dijk (Human Genetics) Description State of the art scientific papers will be handed out and sub-groups will be formed. Use this

time to prepare a short presentation for Tuesday (max. 15 minutes). Literature Understanding therapeutic interventions in lipid metabolism Tuesday, September 23 Theme: Obesity, metabolic syndrome and type-2 diabetes 9.00-9.45 Lecture Title Obesity and metabolic syndrome: etiology Instructor J.A.P. Willems van Dijk (Human Genetics) Description The worldwide epidemic of obesity has led to a dramatic increase in the incidence of the

metabolic syndrome (MetS). The definition of the MetS is somewhat controversial but is characterized by the co-occurrence of multiple metabolic and vascular risk factors. The MetS is associated with an increased risk for the development of type 2 diabetes mellitus and cardiovascular disease. It is thus anticipated that obesity-associated morbidity and mortality will develop into a formidable financial and social burden in the near future. In this lecture, we will address the role of genes and environment in the development of obesity and associated pathology. We will discuss insight in the development of obesity and associated pathology from both human and animal research.

Literature Selected review: • Harmonizing the metabolic syndrome: a joint interim statement of the International

Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Alberti KG et al. Circulation 2009, 120: 1640-5.

Preparation Reading of the literature 10.00-10.45 Lecture Title T2DM: prevention and treatment Instructors H. Pijl (Endocrinology) Description Type 2 diabetes mellitus is a serious, complex, multisystem metabolic disease, which is caused

by gene-environment interactions. Accordingly, modulation of environmental determinants can fully prevent the disease and appropriate changes in lifestyle (i.e. nutrition and physical activity) can essentially cure patients who suffer from type 2 diabetes (particularly those who are early on in their disease process). The lecture will outline the pathogenic underpinnings of

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type 2 diabetes and the ensuing lifestyle measures required for prevention and treatment. In addition, I will briefly summarize the contours of drug therapy, which is unfortunately necessary for adequate metabolic control in the majority of patients.

Literature Selected reviews: • Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present

and future. Kahn SE. et al. Lancet 2014, 383: 1068-83. • Prevention and management of type 2 diabetes: dietary components and nutritional

strategies. Ley SH et al. Lancet 2014, 383: 1999-2007. Preparation Reading of the literature 11.00-12.00 Debate Title Discussion on topics in lipid metabolism, MetS and T2DM Instructors P.C.N. Rensen (Endocrinology)/ J.A.P. Willems van Dijk (Human Genetics) Description Challenging propositions will first be discussed in small groups, followed by plenary

discussion. 13.30-17.00 Workgroup Title Paper presentation and discussion session II Instructor P.C.N. Rensen (Endocrinology) Description Understanding therapeutic interventions in lipid metabolism Literature Has been handed out on Monday, September 22 Preparation Short presentation of max. 15 minutes Wednesday, September 24 Theme: Atherosclerosis 9.00-9.45 Lecture Title Human atherosclerosis and experimental models Instructor J.F.P. Berbée (Endocrinology) Description A short background will be given on the etiology and classification of atherosclerosis. Recent

insights in factors involved in atherosclerosis will be highlighted and various experimental models that are available to study mechanisms of atherosclerosis development and to test the efficacy of experimental drugs will be discussed.

Literature Text book: • McPhee (6th edition): Chapter 11: page 296-300.

Selected reviews: • Progress and challenges in translating the biology of atherosclerosis. Libby P et al.

Nature 2011, 473: 317-25. • Mouse models for atherosclerosis and pharmaceutical modifiers. Zadelaar S et al.

Arterioscler Thromb Vasc Biol 2007, 27: 1706-21. Preparation Reading of the literature 10.00-10.45 Workgroup Title Critical parameters for patients at risk Instructor M.V. Huisman (STOL) Description Defining risk factors and treatment strategies for atherosclerosis. Literature Selected review:

• Ultrasound and radiology surrogate endpoints in pharmacological studies. Agewall S et al. Atherosclerosis 2012, 224: 12-24

Preparation Reading of the literature 11.00-12.00 Patient demonstration Title Understanding endpoints in atherosclerosis Instructor M.V. Huisman (STOL) Description A patient will be demonstrated with risk factors of atherosclerosis: obesity, diabetes,

hypertension. The question will be discussed whether measurement of the intima media thickness (IMT) will provide additional information for assessing cardiovascular risk.

Literature Text book:

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• Harrison’s Textbook of Medicine 18th version (Chapter 241): The Pathogenesis, Prevention and Treatment of Atherosclerosis (Peter Libby). The online version is freely available via the Walaeus library.

Selected reviews: • Measurement of carotid intima-media thickness to assess progression and regression

of atherosclerosis. De Groot E et al. Nat Clin Pract Cardiovasc Med 2008, 5: 280-8. • Prediction of clinical cardiovascular events with carotid intima-media thickness: a

systematic review and meta-analysis. Lorenz MW et al. Circulation 2007, 115: 459-67.

Preparation Reading of the literature 13.30-17.00 Practical work Title Vascular pathology Instructors J.F.P. Berbée, Y. Wang (Endocrinology) Description A short lecture will be given discussing atherosclerotic lesion classification by histology

according to the American Heart Association (from initial Type I to advanced Type VI lesions). Subsequently, students will be divided into small groups and classify and discuss atherosclerotic lesions from various (intervention) studies.

Literature Selected reviews: • A definition of advanced types of atherosclerotic lesions and a histological

classification of atherosclerosis. Stary HC et al. Circulation 1995, 92: 1355-74. • Lessons from sudden Coronary death: A comprehensive morphological classification

scheme for atherosclerotic lesions. Virmani R et al. Arterioscler Thromb Vasc Biol 2000, 20: 1262-75.

Thursday, September 25 Theme: Pathogenesis of atherosclerosis: inflammation 9.00-9.45 Lecture Title Introduction inflammation Instructor V. van Harmelen (Endocrinology) Description Obesity is closely associated with insulin resistance, type 2 diabetes (T2DM), dyslipidemia,

hypertension and cardiovascular disease. Expanding white adipose tissue plays an important role in the pathophysiology of obesity-associated disorders as it responds to the energy overload with stress signals which in turn can elicit local immune responses and inflammation. In this the underlying mechanisms for inflammation in white adipose tissue will be described.

Literature Selected reviews: • Lean, but not obese, fat is enriched for a unique population of regulatory T cells that

affect metabolic parameters. Feuerer M et al. Nat Med. 2009, 15: 930-9. • CD8+ effector T cells contribute to macrophage recruitment and adipose tissue

inflammation in obesity. Nishimura S et al. Nat Med. 2009, 15: 914-20. • Normalization of obesity-associated insulin resistance through immunotherapy. Winer

S et al. Nat Med. 2009, 15: 921-9. • B cells promote insulin resistance through modulation of T cells and production of

pathogenic IgG antibodies. Winer DA et al. Nat Med. 2011, 17: 610-7. Preparation Reading of the literature 10.00-10.45 Lecture Title Vascular inflammation Instructor J. Kuiper (LACDR, Biopharmaceutics) Description The lecture will provide an overview of the role of inflammatory and immune responses in

atherosclerosis. It will focus on innate and adaptive immune responses that are involved in the various stages of atherosclerosis and the effect of enhanced cholesterol levels on these processes.

Literature Adaptive immunity in atherogenesis: new insights and therapeutic approaches. Lichtman AH et al. J Clin Invest. 2013; 123: 27-36.

Preparation Reading of the literature. 13.30-17.00 Practical work Title Practical relationship glucose tolerance and body fat

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Instructors J.A.P. Willems van Dijk (Human Genetics), P.C.N. Rensen(Endocrinology) Description Correlating glucose tolerance with body fat Literature NA Friday, September 26 Theme: Molecular Medicine 9.00-9.45 Lecture Title Brain Instructor P.C.N. Rensen (Endocrinology) Description The brain, and in particular the hypothalamus, plays a central role in lipid and glucose

metabolism by sensing hormones and nutrients derived from various peripheral tissues including the pancreas (insulin), gut (incretins), and white adipose tissue (leptin). The effects of central signalling under insulin sensitive and insulin resistant conditions on peripheral lipid and glucose metabolism will be discussed.

Literature Review: • Targeting the CNS to treat type 2 diabetes. Sandoval DA et al. Nat Rev Drug Discov

2009, 8: 386-98. Preparation Reading of the literature. 10.00-10.45 Lecture Title Brown fat Instructor M.R. Boon (Endocrinology) Description Brown adipose tissue (BAT) is a highly metabolically active tissue that combusts triglyceride-

derived fatty acids towards heat, resulting in enhanced energy expenditure. BAT activity is inversely related to obesity and fat mass, suggesting that enhancing BAT activity is a promising tool to combat obesity and related disorders. Indeed, 6 weeks of cold acclimation, a major trigger of BAT activity lowers fat mass in adult humans (Yoneshiro et al., JCI 2013). Current research focuses on enhancing the understanding of BAT physiology in humans, as well as identifying novel BAT activating compounds.

Literature Selected reviews: • Energy dissipation in brown adipose tissue: from mice to men. Vosselman MJ et al.

Mol Cell Endocrinol 2013, 379: 43-50. • Does irisin have a bright future as a therapeutic agent in humans? Irving BA et al.

Curr Obes Rep 2014, 3: 235-41. Preparation Reading of the literature. 11.00-11.45 Lecture Title Microbiome Instructor J.A.P. Willems van Dijk (Human Genetics) Description The microbiome, encoded by all microorganisms in and on our body, has also been termed our

second genome. For example, there are 10 times more bacteria in our gut than we have cells. These bacteria are not just bystanders, but function in the harvest of energy from our food and play a role in the development and maintenance of the immune system. Gut microbiota have been associated with metabolic and immune disorders and could function as targets for intervention. In this lecture, recent insight into the role of gut microbiota in metabolic and cardiovascular disease will be discussed.

Literature Selected review: • The gut microbiota: masters of host development and physiology. Sommer F and

Bäckhed F. Nat Rev Microbiol 2013, 11: 227-38. Preparation Reading of the literature 13.00-17.00 Self-study Title Blog update Instructor Assigned mentor Description Use this time to work on your blog and case report

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Week 5 Macrovascular disease: atherosclerosis 2

Clinical coordinators Pijl Topics LE Lecture Scientific coordinators Rensen, Willems van Dijk Cerebrovascular incident, central mechanisms SS Self Study

Genetics and epidemiology DE Demonstration Other teachers involved de Mutsert The Neo study WO Workgroup

Meijer, Lammers Central mechanisms and stress PR Practical workMook, van Zonneveld Novel biomarkers in cardiovascular disease DB Debatevan KlinkenWermer

Monday Cerebro-vascular incident central mechanisms29-Sep

9.00-9.45 LE Stroke Stroke, causes and complications V4-62 Wermer9.45-10.00 Break

10.00-10.45 LE Stroke, imaging Imaging and diagnosis of stroke V4-62 Wermer

10.45-11.00 Break11.00-12.00 LE Stroke Management of cerebrovascular incident V4-62 Wermer

12.00-13.30 Lunch

13.30-17.00 SS A state of the art scientific paper V4-62

Tuesday Genetics and Epidemiology30-Sep

9.00-9.45 LE Introduction understand monogenic and polygenic disease V2-10/14 Willems van Dijk9.45-10.00 Break

10.00-10.45 LE Novel DNA/RNA based interventions

insight in novel therapeutic approaches V2-10/14 Willems van Dijk

10.45-11.00 Break11.00-12.00 LE Epidemiology - NEO understand use epidemiology in prediction and prevention V2-10/14 de Mutsert12.00-13.30 Lunch13.30-17.00 WO Paper presentations V2-10/14 Rensen, Willems v. D

Wednesday Central mechanisms01-oct

9.00-9.45 LE Sleep deprivation/circadian rhythm

Role circadian rhythm in MetS V3-36 Biermasz

9.45-10.00 Break10.00-10.45 LE Stress Role stress in MetS V3-36 Meijer

10.45-11.00 Break11.00-12.00 DB Case examples how to interpret case reports V3-36 Lammers

Thursday Molecular medicine02-oct

9.00-9.45 LE Metabolomics/Personalized medicine

How to use metabolomics for personalized medicine CZ-2 Mook

9.45-10.00 Break10.00-10.45 LE Novel biomarkers for risk

predictionUse of biomarkers for risk prediction CZ-2 van Zonneveld

10.45-11.00 Break11.00-12.00 WO Pathway interpretation and

visualization (on line)How to interpret and visualize metabolic pathways CZ-2 van Klinken

12.00-13.00 Lunch13.00-17.00 SS Writing a (short) blog Use this time to work on your blog home/library

Friday03-oct Leidens ontzet

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Week 5: Macrovascular disease 2 Coordinator(s): Willems van Dijk, Rensen, Pijl Teachers: Wermer, Havekes, Berbee, Boon, de Mutsert, Biermasz, van Klinken, van Walderveen, Kruyt Outline In macrovascular disease part II you will be introduced to another set of risk factors associated with the central nervous system that are related to the development of atherosclerosis. Also with the Leiden based “Netherlands Epidemiology of Obesity Study” as an example we will discuss the importance of epidemiology in prediction and prevention. Automatically leads to the topic of biomarkers that are central to prediction and diagnosis of patients at risk for cardiovascular disease. Several innovative approaches to identify and detect biomarkers will be presented. The week will start with introduction of another clinical manifestation of atherosclerosis, the cerebrovascular incident Topics

• Cerebrovascular incident, central mechanisms • Genetics and epidemiology • The Neo study • Central mechanisms and stress • Novel biomarkers in cardiovascular disease

Evaluation


Day to Day program Monday, September 29 Theme: Cerebrovascular incident, central mechanisms 9.00-9.45 Lecture Title Stroke Instructors M. Wermer (Neurology) Description Stroke is prevalent in the Western World, and is related to traditional risk factors of

atherosclerosis such as hypertension and smoking. It is caused by insufficient blood supply to the brain, which in turn may result from abrupt blockage of afferent cerebral arteries (ischemic stroke) or bleeding after vascular rupture (hemorrhagic stroke). Novel insights into the etiological mechanisms are discussed

Literature Kumar, Abbas en Fausto and Clark Selected papers will be handed out

Preparation Reading the literature 10.00-10.45 Lecture Title Stroke, imaging Instructor M. van Walderveen (Neuroradiology) Description Imaging of the brain is of extreme importance in clinical stroke care. It is used for precise

diagnosis as well as planning for therapeutic interventions. The state of the art of brain imaging is discussed.

Literature Kumar, Abbas en Fausto and Clark Selected papers will be handed out

Preparation Reading the literature 11.00-12.00 Lecture Title Management of cerebrovascular incident: prevention and treatment Instructor N Kruyt (Neurology), M. Wermer (Neurology)

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Description At the onset of stroke, rapid restoration of cerebral blood flow is of the utmost importance. Care for stroke patients is organized in care tracks. The medical and interventional treatment modalities are discussed

Literature Basic: Kumar, Abbas en Fausto and Clark Preparation Reading the literature. 13.30-17.00 Self-study Title State of the art scientific paper session III Instructor Description State of the art scientific papers will be handed out and sub-groups will be formed. Use this

time to prepare a short presentation for Tuesday (max 15 minutes) Tuesday, September 30 Theme: Genetics and epidemiology 9.00-9.45 Lecture Title Epidemiology: the NEO study Instructors Renée de Mutsert (Clinical Epidemiology) Description Overweight and obesity are well-established risk factors for the development of type 2

diabetes mellitus and cardiovascular disease. However, the etiology of these obesity-related diseases is much less well understood. At the LUMC, a large prospective study has been initiated to investigate the pathways that lead to disease in persons with overweight and obesity. This study as well as the epidemiological tools to address disease associations will be discussed.

Literature Gast KB et al. Abdominal adiposity largely explains associations between insulin resistance hyperglycemia and subclinical atherosclerosis: the NEO study. Atherosclerosis 2013; 229:423-429 De Mutsert et al. The Netherlands Epidemiology of Obesity (NEO) study: study design and data collection. Eur J Epidemiol 2013;28:513-523

Preparation Reading the literature 10.00-10.45 Lecture Title Introduction in genetics Instructor J.A.P. Willems van Dijk (Human genetics) Description Both type 2 diabetes and cardiovascular disease are highly heritable as evidenced by the

dramatically increased risk for subjects with young affected relatives in the first degree. These genetic risks can roughly be divided in monogenic and complex genetic disease. In this lecture, examples of both types of disease and their interaction with environmental factors will be discussed.

Literature Turnpenny 7 Ellard: Emery’ s elements of medical genetics, 12e druk. BW students: Thompson&Thompson, Genetics in Medicine, p360-364: Familial Hypercholesterolemia: a genetic hyperlipidemia.

11.00-12.00 Lecture Title Novel DNA/RNA based interventions Instructors J.A.P. Willems van Dijk (Human genetics) Description Mechanistic insight in the biochemical basis of genetic disease has provided the basis for novel

therapeutic interventions. In this lecture, we will discuss a.o. the discovery of PCSK9, an inhibitor of the receptor that is responsible for clearance of LDL-cholesterol from the circulation. This discovery and subsequent characterization of its action has led to a variety of novel drugs that inhibit PCKS9. These include small molecules, but also inhibitors of transcription and translation.

Literature Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res 2012; 53(12):2515–24

13.30-17.00 Workgroup Title Paper presentation and discussion session III

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Wednesday, October 1 Theme: Central mechanisms 9.00-9.45 Lecture Title Sleep deprivation/circadian rhythm Instructor N.R. Biermasz (Endocrinology) Description Sleep and circadian rhythm are increasingly recognized as important players in metabolic

health. There is a clear association between (shorter) sleep duration and obesity, insulin resistence and cardiovascular mortality. Also shift work has been related to adverse glucose and lipid metabolism. In this lecture we will discuss the function of the central and peripheral biological clocks, and effects of circadian and sleep disruption on metabolism and development of the metabolic syndrome.

Literature Bass et. Al. Science 2010, 330,1349 Preparation 10.00-10.45 Lecture Title Circadian integration of metabolism and energetics Instructor O.C. Meijer (Endocrinology) Description Stress is a state we enter when demands on the body exceed normal homeostatic control.

Coping with the challenges that cause stress requires energy. An important component of the stress response is therefore the recruitment of energy stored a glycogen, fat or - if necessary - proteins. Both sympathetic nervous system activity and glucocorticoid stress hormones contribute to the recruitment of energy. This is all fine and adaptive, if the energy is indeed used to support adaptation to the stressor. Modern man also suffers from stressors that do not require vast amounts of energy: many psychological stressors activate the stress response and lead to liberation of energy. However, no 'fight' or 'flight' response is mounted, but rather rumination and worry. The resultant can be 1) that the energy liberated from glycogen, fat and protein has to be stored again as fat, and 2) that the increased glucose levels caused by activation of the stress hormones contribute to insulin resistance. We will discuss how these mechanisms - which are in principle adaptive in many situations - may contribute to the development of metabolic syndrome.

Literature Laryea G, Schütz G, Muglia LJ. Disrupting hypothalamic glucocorticoid receptors causes HPA axis hyperactivity and excess adiposity. Mol Endocrinol. 2013 27(10):1655-65

11.00-11.45 Debate Title Case examples Instructor N.R. Biermasz (Endocrinology) Description In this lecture, we will discuss examples of patients with disturbed rythms and associated

problems with metabolic and cardiovascular disease. Thursday, October 2 Theme: Molecular medicine 9.00-9.45 Lecture Title Metabolomics Instructor Dr. Dennis Mook (Endocrinology) Description Metabolites are small molecules that are generated or consumed in enzymatic reactions. As

such, metabolites are the intermediaries between the host genetic make-up and environmental exposure, and the disease endpoints. Technological developments have made it possible to measure hundreds of metabolites in tissues and bodily fluids. In this lecture we will discuss the genetics and additional value of metabolomics in understanding and predicting disease.

Literature Illig T. et al. A genome-wide perspective of genetic variation in human metabolism. Nat Genet. 2010, 42(2):137-41

Preparation 10.00-10.45 Lecture Title Circulating cells as biomarkers for risk prediction Instructor A.J. van Zonneveld (Nephrology) Description Monocytes are cells of the innate immune system that circulate in blood in various subsets. In

patients with chronic, systemic inflammation a subset of monocytes that are pro-inflammatory

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and pro-atherogenic is increased and the number of these cells directly correlate with CVD. The increase in pro-inflammatory monocytes comes at the cost of the generation of the generation of monocytes involved in vascular repair. Using innovative microRNA profiling techniques we aim to develop a novel diagnostic approach that can assess the phenotype of circulating monocytes and help determine the risk for the progression of atherosclerosis.

Literature Preparation Woollard, K. & Geissmann, F. Monocytes in atherosclerosis: subsets and functions. Nat Rev

Cardiol. 7, 1-19 (2010) 11.00-12.00 Workgroup Title Pathway interpretation and visualization (on line) Instructor J.B. van Klinken (Human Genetics) Description Pathway analysis has become an indispensable tool in the analysis and interpretation of large,

omics datasets. In this practical session we will analyse gene expression data measured in human adipocyte tissue by using a number of pathway tools that have been made available on the internet.

Literature Khatri P, Sirota M, Butte AJ. Ten years of pathway analysis: current approaches and outstanding challenges. PLoS Comput Biol. 2012;8(2):e1002375.

Preparation NA 13.00-17.00 Self-study Title Blog update Instructor Assigned mentor Description Use this time to work on your blog and case report Literature NA Preparation NA Friday, October 3 Theme: Free “Leidens ontzet”

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Week 6 Clinical diagnosis and therapy

Clinical coordinators Atsma Topics LE Lecture Scientific coordinators Pijnappels ACS SS Self Study

Heart failure DE Demonstration Other teachers involved Jukema Arrhythmia's WO Workgroup

Beeres, Steendijk, Verwey Imaging techniques PR Practical workde Grooth, van der Kley Conventional therapies (angioplasty, bypass, medication) DB DebateAlizadeh, Zeppenfeld Experimental models for neointimal hyperplasiaVander Veer, de Vries

Monday Acute coronary syndrome and heart failure06-Oct9.00-9.45 LE Introduction by the block

coördinatorsV3-36 Atsma, Pijnappels

9.45-10.00 Break10.00-10.45 LE Acute coronary syndrome The spectrum of acute coronary syndrome in relation to the

underlying pathophysiological processV3-36 Jukema

10.45-11.00 Break11.00-12.00 LE Heart failure Discussion on the pathofysiology of heart failure V3-36 Beeres, Steendijk,

Verwey12.00-13.30 Lunch

13.30-15.30 SS A state of the art scientific paper

Anticoagulants in stents V4-50 Atsma, de Grooth, Jukema

Tuesday Clinical management of ACS07-Oct9.00-9.45 PD patient demonstration ACS history V2-26/28 Atsma

9.45-10.00 Break10.00-10.45 LE ACS Clinical management of stable angina pectoris CZ-2 Jukema10.45-11.00 Break11.00-12.00 LE ACS Interventional management of ACS CZ-2 de Grooth, van der

Kley12.00-13.30 Lunch13.30-15.30 WO Paper presentations anticoagulants in stents V2-18/22 Atsma, de Grooth,

Jukema

Wednesday Cardiac arrhytmias08-Oct

9.00-9.45 LE Arrhythmia's Treatment options for supraventricular arrhytmia's V3-36 Alizadeh, Zeppenfeld

9.45-10.00 Break

10.00-10.45 LE Arrhythmia's Treatment options for ventricular arrhytmia's V3-36 Alizadeh, Zeppenfeld

10.45-11.00 Break11.00-12.00 DE Cathlab visit the Cathlab V3-36 Atsma12.00-13.30 Lunch13.30-15.30 DE Cathlab visit the Cathlab V2-34 Atsma

Thursday Molecular Medicine09-Oct

9.00-9.45 LE Neointimal hyperplasia Role of RNA binding protein Quaking in neointimal hyperplasia V3-22 van der Veer

9.45-10.00 Break10.00-10.45 LE Arrhytmia's Molecular therapy for arrhythmia V3-22 de Vries

10.45-11.00 Break13.00-17.00 SS Writing a (short) blog Use this time to work on your blog home/library

Friday Exam10-Oct

11.00-12.00 EX knowledge test 2 Covering week 4-6 V3-36

Covering week 1-6

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Week 6: Clinical diagnosis and therapy Coordinator(s): Atsma, Pijnappels Teachers: Beeres, Steendijk, Verwey, de Grooth, van der Kley, Alizadeh, Zeppenfeld, van der Veer, de

Vries, Jukema Outline This week we will focus on the clinical manifestations of common cardiovascular disease and their contemporary management. Patients will be demonstrated with specific cardiac disease (angina pectoris, heart failure, arrhythmia’s, peripheral artery disease). We will discuss the clinical picture in relation to the (molecular) pathophysiological concepts that have been learned earlier. Current state of the art therapies will be discussed. In addition, we will outline experimental treatments some of which will be demonstrated in the last week Topics

• Understand the clinical manifestations of angina pectoris, heart failure and cardiac arrhythmia’s.

• Understand the pathophysiology of angina pectoris, heart failure and cardiac arrhythmia’s. • Understand the state of the art in therapies, as well as of novel therapeutic concepts. • Perform literature research and present the learned concepts in a presentation

Evaluation


Day to Day program Monday, October 6 Theme: Acute coronary syndrome and heart failure 9.00-9.45 Introduction Title Introduction by the block coordinators Instructor D.E. Atsma, D.A. Pijnappels (Cardiology) Description This lecture will give an overview of the various topics that will be dealt with in this week. 10.00-10.45 Lecture Title Acute coronary syndrome Instructor J.W. Jukema (Cardiology) Description Coronary artery disease is still a major cause of morbidity and mortality in the Western world.

Coronary anatomy will be discussed, as well as the mechanisms for acute thrombus formation on atherosclerotic plaques. The whole spectrum of acute coronary syndrome (ACS) will be highlighted in relation with the various underlying pathophysiologic processes.

Literature Basic: Kumar, Abbas en Fausto and Clark 11.00-12.00 Lecture Title Heart failure Instructor S.L.M.A Beeres/P. Steendijk/H.F. Verwey Description Heart failure may result from ischemic heart disease but also hypertension or genetic

mutations. This spectrum of disease will be discussed Literature Basic: Kumar, Abbas en Fausto and Clark 13.30-17.00 Workgroup Title Paper presentation and discussion session IV Instructor D.E.Atsma (Cardiology) Literature Anticoagulants in stents

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Tuesday, October 7 Theme: Clinical management of ACS 9.00-9.45 Patient demonstration Title Patient with history of ACS Instructor D.E. Atsma (Cardiology) Description We will demonstrate a patient with coronary artery disease to discuss the symptoms of the

patient in relation to the results obtained in the various tests that are available for this patient. 10.00-10.45 Lecture Title Clinical management of stable angina pectoris Instructors F. van der Kley Description Medication and modification of life style are pivotal interventions in the treatment of stable

angina. Various drug classes are used to treat stable angina, including platelet inhibitors, betablockers, calcium antagonists, nitrates, ACE inhibitors and statins. Novel drugs include If inhibitors like ivabradine. We will discuss state of the art medical management of stable angina pectoris and discuss new developments.

Literature Basic: Kumar, Abbas en Fausto and Clark Preparation Reading the literature 11.00-11.45 Lecture Title Interventional management of ACS Instructors F. van der Kley, G. de Grooth, (Cardiology) Description If medical treatment for angina pectoris is insufficient, mechanical revascularization will be

attempted. In general there are percutaneous as well as surgical options. Catheter-based intervention includes Percutaneous Coronary Intervention (PCI), with rapid developments in balloon and stent-design. Recent developments include the coating of stents with anti-proliferative drugs to reduce the restenosis probability. Coronary Artery Bypass Grafting (CABG) is the surgical approach to restore myocardial blood flow. The state of the art for coronary revascularization will be discussed.

Literature Basic: Kumar, Abbas en Fausto and Clark 13.30-17.00 Workgroup Title Paper presentation and discussion session IV Instructor G. de Grooth, J.W. Jukema (Cardiology) Description Anticoagulation in stents: the optimal strategy for anticoagulation after PCI depends on patient

characteristics as well as stent properties. The various scenario’s will be presented by the students.

Preparation Reading the handed out papers en prepare a presentation. Wednesday, October 8 Theme: Cardiac arrhythmias 9.00-9.45 Lecture Title Treatment options for supraventricular arrhythmia’s Instructor K. Zeppenfeld, R. Alizadeh (Cardiology) Description Supraventricular arrhythmia’s are a common problem in Cardiology, that can have a

profound negative impact on patients’ quality of life. The treatment of the various kinds of supraventricular arrhythmia’s will be discussed, ranging from preventive measures (e.g. oral anticoagulation), anti-arrhythmic drugs or RF-ablation.

Literature Basic: Kumar, Abbas en Fausto and Clark Preparation Reading the literature 10.00-10.45 Lecture Title Treatment options for ventricular arrhythmia’s Instructor K. Zeppenfeld, R. Alizadeh (Cardiology) Description Ventricular arrhythmia’s, and more specifically ventricular tachycardia (VT) constitute a

potentially lethal affliction. Various etiologies may underlie VT, with different mechanisms. These mechanisms may require tailored treatment strategies, both medical and interventional.

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Image fusion techniques are used to identify VT mechanisms and to target treatment like RF ablation. The current therapeutic LUMC concepts are discussed.

Literature Basic: Kumar, Abbas en Fausto and Clark Chapter. State of the art papers will be provided. Preparation Reading the literature 11.00-12.00 Demonstration Title A visit to the cathlab Instructor D.E. Atsma (Cardiology) Description Cases will be demonstrated including PCI and RF ablation. 13.30-15.30 Demonstration Title A visit to the cathlab Instructors D.E. Atsma (Cardiology) Description Cases will be demonstrated including PCI and RF ablation. Thursday, October 9 Theme: Molecular Medicine 9.00-9.45 Lecture Title Neointimal hyperplasia Instructor E.P. van der Veer Description RNA-binding proteins are critical post-transcriptional regulators and can influence pre-mRNA

splicing, mRNA localization, and stability. The RNA-binding protein Quaking (QKI) is essential for embryonic blood vessel development. The RNA-binding protein Quaking (QKI) is highly expressed by neointimal VSMCs of human coronary restenotic lesions, but not in healthy vessels. We demonstrated that QKI is a central regulator of VSMC phenotypic plasticity and that intervention in QKI activity can ameliorate pathogenic, fibroproliferative responses to vascular injury.

Preparation Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell

phenotype. Van der Veer et al. Circ Res. 2013 Oct 12;113(9):1065-75 10.00-10.45 Lecture Title Molecular therapy for arrhythmia Instructor A.A.F. de Vries (Cardiology) Description Influencing the basis electrophysiological properties of cardiomyocytes may decrease their

propensity to form re-entry circuits, and thus, arrhythmia’s. Novel molecular strategies will be discussed that could potentially be used as biological treatment options.

Literature State of the art papers will be provided. Preparation Reading the provide literature. 13.00-17.00 Self-study Title Blog update Instructor Assigned mentor Description Use this time to work on your blog and case report Friday, October 10 Theme: Exam 11.00-12.00 Exam Title Knowledge test 2 Description Covering week 1-6

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Week 7 Vascular surgery and peripheral artery disease

Clinical coordinators Hamming Topics LE Lecture Scientific coordinators Quax Introduction in vascular surgery SS Self Study

Vascular remodeling DE Demonstration Other teachers involved Schepers, de Vries Angioplasty and veingrafts WO Workgroup

Lindeman Aneurysma's PR Practical workRotmans, Rothuizen Vascular access in CKD DB DebateChun Yu WongNossent

Monday Introduction in Vascular Surgery13-Oct9.00-9.45 LE Introduction by the block Introduction in vascular surgery, what does vascular surgion encounter in clinical V4-50 Hamming

9.45-10.00 Break10.00-10.45 LE Arteriogenesis 1 Vascular remodeling and collateral formation is essential for adaptation of the

V4-50 Quax

10.45-11.00 Break11.00-12.00 LE Arteriogenesis 2 Inflammation, immune modulation and therapeutic options V4-50 Quax12.00-13.30 Lunch13.30-15.30 DE Live surgery The vascular surgions operation theatre (live connection with the OR) V4-50 Hamming, Schepers

Tuesday Post-interventional vascular remodeling14-Oct9.00-9.45 LE Restenosis Reocclusion after balloon angioplasty V4-50 Quax

9.45-10.00 Break10.00-10.45 LE Vein graft disease Failure of vein grafts V4-50 de Vries10.45-11.00 Break

11.00-12.00 WO A state of the art scientific paper V4-50

Wednesday Aneurysma15-Oct

9.00-9.45 LE Aneurysma 1 Clinical management of aneurysms V4-50 Schepers9.45-10.00 Break

10.00-10.45 LE Aneurysma 2 Pathophysiology of aneurysm V4-50 Lindeman10.45-11.00 Break11.00-12.00 DE Introduction on the debate V4-50 Lindeman12.00-13.30 Lunch

13.30-15.30 DE Population screening for aneurysm yes or no? V4-50 Lindeman

Thursday Vascular access failure16-Oct

9.00-9.45 LE Vascular access in CKD Clinical management of arterial venous fistula's V4-50 Rotmans9.45-10.00 Break

10.00-10.45 LE Vascular access in CKD Experimental approaches in vascular access V4-50 Chung Yu Wong10.45-11.00 break11.00-12.00 WO presentation of papers V4-50

Friday Molecular medicine17-Oct

9.00-9.45 LE Vascular remodeling Mirs in vascular remodeling V4-50 Nossent9.45-10.00 Break

10.00-10.45 LE peripheral artery disease Novel clinical options inperipheral artery disease V4-50 Quax

10.45-11.00 Break11.00-12.00 LE Vascular access Tissue engineering of vascular access grafts V4-50 Rotmans

12.00-13.00 Lunch13.00- 17.00 SS Writing a (short) blog Use this time to work on your blog home/library

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Week 7: Vascular surgery and peripheral artery disease

Coordinator(s): Hamming, Quax Teachers: Schepers, de Vries, Lindeman, Rotmans, Rothuizen, Chun Yu Wong, Visser, Nossent Outline The main goal of this week of the course is to review the most important aspects in vascular surgery, both from a clinical point of view by clinicians and from a preclinical pathophysiological point of view by the researchers. Students will attend via live video connection vascular surgical operations, and the surgeons will comment on the procedure during these operations. In parallel the pathophysiology of most addressed topics in vascular surgery and peripheral artery disease will be discussed in lectures and workgroups. The topics comprise the vascular surgery in relation to vascular remodeling in aneurysm formation, atherosclerosis, restenosis, vein graft disease, dialysis vascular access, vascular tissue engineering and neovascularization in therapeutic angiogenesis approaches. The students will obtain a better view on how current challenges in clinics can be translated into research projects in order to better define the pathophysiology and new therapeutic options. Topics

• Introduction in vascular surgery • Vascular remodelling • Angioplasty and vein grafts • Aneurysma’s • Vascular access in CKD

Evaluation • Evaluation of blog contribution • Multiple choice exam week 9 • Evaluation of paper presentation

Day to Day program Monday, October 13 Theme: Introduction in vascular surgery 9.00-9.45 Introduction Title Introduction in vascular surgery, what vascular surgeon can encounter in clinical practise ? Instructor J.F. Hamming (Surgery) Description This lecture will give an introduction in vascular surgery, various aspects of vascular surgery

will be introduced, including aneurysms, peripheral arterial disease and construction of dialysis vascular access. In principle this lecture will provide a reflection of what a vascular surgeon can encounter in daily clinical practise

Literature not applicable Preparation not required 10.00-10.45 Lecture Title Arteriogeness 1 Instructor P.H.A. Quax (Surgery) Description Vascular remodeling and collateral formation is essential for adaptation of the vascular system.

In patients with hampered blood flow to their limbs, e.g. patients with severe peripheral arterial disease, neovascularization can be induced for therapeutic purposes. In this lecture the principles of arteriogenesis and collateral formation will be discussed.

Literature General background information: Kumar, Abbas en Fausto and Clark , Pathology of Disease,Chapter 11, Blood Vessels, Mitchell and Schoen , p 487-529

Preparation Read background literature 11.00-12.00 Lecture Title Arteriogenesis 2 Instructor P.H.A. Quax (Surgery)

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Description Vascular remodeling and collateral formation is essential for adaptation of the vascular system. In patients with hampered blood flow to their limbs, e.g. patients with severe peripheral arterial disease, neovascularization can be induced for therapeutic purposes. In this lecture the role of inflammation, immune modulation and therapeutic options for neovascularization will be discussed.


13.30-15.30 Demonstration Title Live Surgery Instructor J.F. Hamming/A. Schepers (Surgery) Description The vascular surgeon’s operation theatre (live connection with the OR). In this demonstration

we will follow a vascular surgical operation that is ongoing via a real time video connection with the operation theatre. One of the surgeons will be present in the lecture room and comments on the procedure and will answer question regarding the procedure that is being performed by the colleagues in the surgical theatre. The kind of intervention depends on the schedule of that moment.

Tuesday, October 14 Theme: Post-interventional vascular remodeling 9.00-9.45 Lecture Title Restenosis Instructor P.H.A. Quax (Surgery) Description Atherosclerotic lesion formation may result in the occlusion of (coronary) arteries and

consequently ischemia to the downstream tissue. If this occlusion occurs suddenly, an acute infarction may occur. Balloon Angioplasty is one of the preferred methods to re-open the occluded vessel and restore the blood flow. However, reocclusion of the blood vessel after balloon angioplasty, also called restenosis, occurs frequently and represents a major clinical problem. In this lecture the pathology of restenosis will be discussed as well as several therapeutic and experimental option to reduce restenosis will be discussed.

Literature Preparation Read background literature 10.00-10.45 Lecture Title Vein graft disease Instructors M.R. de Vries (Surgery) Description An alternative, frequently used method to restore the blood flow distal to an occluded blood

vessel is the construction of vascular bypasses for which vein grafts may be used. However, failure of vein grafts, resulting in loss of patency of the bypass graft, occurs frequently. In this lecture the pathology of the processes that lead to vein graft failure will be discussed as well as experimental option to prevent vein graft disease.


Preparation Read background literature 11.00-12.00 Workgroup Title Paper presentation and discussion session V Wednesday, October 15 Theme: Aneurysma 9.00-9.45 Lecture Title Aneurysma 1 Instructor A. Schepers (Surgery) Description In this lecture various aspects of the clinical management of abdominal aortic aneurysms will

be discussed, including various surgical options for treatment such an open repair or endovascular repair procedure

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Preparation Read background literature 10.00-10.45 Lecture Title Aneurysma 2 Instructor J.H.N. Lindeman (Surgery) Description In this lecture the pathophysiology of aneurysm formation will be illustrated and what

consequences this may have for treatment. Literature General background information: Kumar, Abbas en Fausto and Clark , Pathology of Disease,

Chapter 11, Blood Vessels, Mitchell and Schoen , p 487-529 Preparation Read background literature 11.00-12.00 Debate Title introduction to the debate Instructor J.H.N. Lindeman Description Screening of the population for the presence of non-symptomatic abdominal aortic aneurysm is

discussed in several western countries. Such a screening may have advantages but several disadvantages are linked to such a general screening program. This introduction will help you to define the arguments in favour and against such a screening program.

13.30-15.30 Debate Title Debate Instructors J.H.N. Lindeman (Surgery) Description Population screening for aneurysm yes of no? Thursday, October 16 Theme: Vascular access failure 9.00-9.45 Lecture Title Vascular access failure. Instructor J.I. Rotmans (Nephrology) Description Patients with chronic kidney disease usually require dialysis. A proper vascular access in

essential for a good dialysis process in patients with CKD. Arterial venous fistulas are constructed by the vascular surgeons to create such a vascular access. In the current lecture various aspects of the dialysis process will be discussed including the pathology of developing atrial venous fistulas and clinical problems that relate to failing AVFs.

Literature 1. T. Lee et al. Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis. Adv Chronic Kidney Dis 2009. Sep;16(5):329-38

2. T.C. Rothuizen et al. Arteriovenous access failure: more than just intimal hyperplasia? Nephrol Dial Transplant. 2013 May;28(5):1085-92

Preparation read literature 10.00-10.45 Lecture Title Vascular access failure Instructor C.Y. Wong (surgery) Description For dialysis a proper vascular access is required, in which the blood flow is high enough to

guarantee a good dialysis. Arterial venous fistulas are constructed by the vascular surgeons to create such a vascular access. However, these fistula often fail. The pathology of this process is not clear. In the present lecture we will discuss experimental approaches in vascular access and methods to improve the patency of the arterial venous fistulas.

Literature 1. T. Lee et al. Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis. Adv Chronic Kidney Dis 2009. Sep;16(5):329-38

2. T.C. Rothuizen et al. Arteriovenous access failure: more than just intimal hyperplasia? Nephrol Dial Transplant. 2013 May;28(5):1085-92

Preparation read literature

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13.30-17.00 Workgroup Title Paper presentation and discussion session V Friday, October 17 Theme: Molecular medicine 9.00-9.45 Lecture Title MicroRNAs in vascular remodeling Instructor A.Y. Nossent (Surgery) Description Vascular remodelling is a multifactorial, complex regulated process that may be either

pathological, e.g, in case of atherosclerosis or restenosis, or beneficial , e.g. during therapeutic neovascularisation. The topic of the current lecture is the role microRNAs in the regulation of the multifactorial process of vascular remodeling. Furthermore, options for microRNA based therapeutic interventions in vascular remodelding will be discussed.

Literature not applicable Preparation not applicable 10.00-10.45 Lecture Title Novel clinical options in peripheral artery disease Instructor P.H.A. Quax (Surgery) Description Currently patients with end-stage peripheral, when critical limb ischemia results in non-healing

wounds and gangrene, have very limited options for therapy. One of the experimental approaches is the induction of neovascularisation, also called therapeutic angiogenesis. In this lecture several option for therapeutic neovascularisation in patients will be discussed.

11.00-11.45 Lecture Title Tissue engineering of vascular access grafts Instructor T.C. Rothuizen (Nephrology) Description For dialysis a proper vascular access required, in which the blood flow is high enough to

guarantee a good dialysis. Arterial venous fistulas are constructed by the vascular surgeons to create such a vascular access. However, these fistula often fail and alternatives are required. Engineered blood vessels may provide a solution for this problem. In the present lecture various methods will be discussed that are being developed to make new blood vessels

Literature M.A. Cleary. Vascular tissue engineering: the next generation. Trends in Mol. Med., 2012, Vol. 18, No. 7

Preparation read background literature 13.00-17.00 Self-study Title Blog update Instructor Assigned mentor Description Use this time to work on your blog and case report

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Week 8 Microvascular disease

Coordinators Goumans Topics LE LectureCardiovascular complications of type 1 diabetes SS Self StudyPathophysiology of Diabetic Nephropathy DE Demonstration

Other teachers involved De Koning, van Zonneveld Mechanisms in cardiac fibrosis WO WorkgroupDe Fijter, Gaasbeek Rarefaction in Kidney TX and Atrial fibrillation PR Practical workBaelde, Moses Experimal animal models in microvascular disease DB DebateBijkerk, Smits, Abdallah EX Exam

Monday Vascular complication in Diabetes20-oct

9.00-9.45 DE CVD in diabetes Cardiovascular complications of type 1 diabetes: Movie Diabetes Fonds Nederland V2-34 De Koning9.45-10.00 Break10.00-10.45 LE CVD in diabets Pathophysiology of cardiovascular complications in type 1 diabetes V2-34 De Koning10.45-11.00 Break11.00-12.00 LE EPC dysfunction Vascular maintenance and repair is impaired in Diabetes V2-34 van Zonneveld12.00-13.30 Lunch13.30-15.30 DE Retinopathy Fundus foto? V-34 De Koning

Tuesday Cardiovascular complcations in Kidney Disease21-oct

9.00-9.45 CVD in CKD Cardiovascular complications in kidney transplantation V2-34 De Fijter9.45-10.00 Break10.00-10.45 LE Microvascular rarefaction Microvascular rarefaction in diabetes, transplantation and atrial fibrillation V2-34 van Zonneveld10.45-11.00 Break11.00-12.00 DE Dialyses A visit to the dialyses facilities V2-34 Moses, Gaasbeek12.00-13.30 Lunch13.30-15.30 PR Side stream darkfield camera to asses capillary phenotype V2-34 Abdallah

Wednesday Cardiac manifestations of microvascular disease22-oct

9.00-9.45 LE Fibrosis Mechanisms in fibrosis V2-34 Goumans9.45-10.00 Break10.00-10.45 LE Cardiac fibrosis Mechanisms in cardiac fibrosis V2-34 Smits10.45-11.00 Break11.00-12.00 LE Pulmonary hypertension Mechanisms in pulmonary hypertension V2-34 Goumans12.00-13.30 Lunch13.30-15.30 WO novel therapeutic strategies workshop "how would you emloy novel reporters for fibrosis" V2-34 Goumans

Thursday Molecular medicine23-oct

9.00-9.45 LE Diabetic Nephropathy Experimental animal models for diabetic nephropathy V2-34 Baelde9.45-10.00 Break10.45-11.30 Kidney fibrosis in experimental mouse models V2-34 Bijkerk10.30-10.45 Break13.00- 17.00 SS Writing a (short) blog Use this time to work on your blog home/library

Friday No program24-oct

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Week 8: Microvascular disease

Coordinator(s): Goumans Teachers: de Koning, de Fijter, van Zonneveld, Goumans, Baelde, M. Reinders, M. Moses,

Bijkerk Outline The microvasculature comprises up to 80% of the vascular system. While the manifestations of macrovascular obstructions or rupture are mostly leading to acute cardiovascular events, the loss of microvascular integrity often underlies more slowly developing but nevertheless major cardiovascular disease states such as diabetic nephropathy, retinopathy, neuropathies, atrial fibrillation and cardiac fibrosis. The loss or “rarefaction” of the microvascular network is a common denominator in the pathogenesis of these disease states. In this week the major microvascular pathologies will be discussed and experimental model systems to study these traits. Topics

• Cardiovascular complications of type 1 diabetes • Cardiovascular complications of Kidney Disease • Pathophysiology of Diabetic Nephropathy • Mechanisms in cardiac fibrosis and pulmonary hypertension • Rarefaction in Kidney TX and Atrial fibrillation • Experimal animal models in microvascular disease

Evaluation


Day to Day program Monday, October 20 Theme: Vascular complications in diabetes 9.00-9.45 Introduction Title CVD in diabetes Instructor E.J.P. de Koning (Nephrology) Description Cardiovascular complications of type 1 diabetes: Movie Diabetes Fonds Nederland 10.00-10.45 Lecture Title CVD in diabetes Instructor E.J.P. de Koning (Nephrology) Description Pathophysiology of cardiovascular complications in diabetes type 1 Literature Basic: Kumar, Abbas en Fausto and Clark Chapter 11.00-11.45 Lecture Title EPC dysfunction Instructor A.J. van Zonneveld (Nephrology) Description Vascular maintenance and repair is impaired in patients with diabetes mellitus 13.30-15.30 Demonstration Title Retinopathies Instructor E.J.P. de Koning (Nephrology) Tuesday, October 21 Theme: Cardiovascular complications in Kidney Disease 9.00-9.45 Lecture Title Cardiovascular complications in kidney transplantation Instructor H. de Fijter (Nephrology)

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Description Cardiovascular complications in Kidney Disease Literature Basic: Kumar, Abbas en Fausto and Clark 10.00-10.45 Lecture Title Microvascular rarefaction in diabetes, transplantation and atrial fibrillation Instructors A.J. van Zonneveld Literature Basic: Kumar, Abbas en Fausto and Clark 11.00-11.45 Demonstration Title A visit to the dialyses department Instructors M. Moses, Dr. A. Gaasbeek (Nephrology) 13.30-15.30 Practical work Title SDF camera Instructors Abdallah (Nephrology) Description Side stream darkfield camera to asses microvascular tortuosity Wednesday, October 22 Theme: Manifestations of microvascular disease 9.00-9.45 Lecture Title Mechanisms in fibrosis Instructor M.J.T.H. Goumans (Mol Cell Biology) Description The loss of tissue perfusion is a rate limiting mechanism in the progression of fibrosis and end-

organ failure. Fibrosis is an essential process of proper wound healing. It is the end result of a succession of events that occur after mechanical damage to the epithelium or endothelium. Fibrotic diseases may be attributable to a variety of causes, but it is generally thought that an initiating injury event activates repair processes that aim to restore the original tissue architecture, and a failure to finely tune the repair process leads to persistent fibroblast activation and tissue destruction. The predominant cellular mediator of fibrosis is assumed to be the myofibroblast. The origin of these myofibroblasts may, besides resident interstitial fibroblasts, be cells derived from the bone marrow as well as fibroblastic cells that have transdifferentiated from cells of endothelial or epithelial origin. There are key growth factor pathways involved in physiological and pathological fibrosis, of which TGFβ is an important one. These pathways, as well as the origin of the fibrotic cells will be discussed.

Literature Basic: Kumar, Abbas en Fausto and Clark Preparation Read literature 10.00-10.45 Lecture Title Cardiac fibrosis Instructor A.M. Smits (Mol Cell Biology) Description Mechanisms in cardiac fibrosis The contribution of fibrogenesis to impaired cardiac function is increasingly recognized. The

fibrotic ECM causes increased stiffness and induces pathological signalling within cardiomyocytes resulting in progressive cardiac failure. Also, the excessive ECM impairs mechano-electric coupling of cardiomyocytes and increases the risk of arrhythmias. Fibroblasts are principally responsible for deposition of the excessive fibrotic ECM and activated fibroblasts may directly cause hypertrophy of cardiomyocytes via paracrine mechanisms further contributing to impaired cardiac function. Fibrosis manifests in two forms, that is, reactive interstitial fibrosis or replacement fibrosis. In animal models of left ventricular pressure overloading, reactive interstitial fibrosis is observed which progresses without loss of cardiomyocytes. This initial reactive interstitial fibrosis is an adaptive response aimed to preserve the pressure generating capacity of the heart but will progress into a state of replacement fibrosis, characterized by cardiomyocyte hypertrophy and necrosis. On the other hand, in animal models of acute myocardial infarction, an initial inflammatory reaction is followed exclusively by myocyte death and replacement fibrosis. Although both animal models represent certain stages and mechanisms of human cardiopathy, they also show distinct and non-overlapping fibroblast reactions. This will be discussed during the lecture.

Literature Basic: Kumar, Abbas en Fausto and Clark Chapter?

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J Cell Physiol. 2010 Nov;225(3):631-7. Weber, Circulation. 1997 Dec 2;96(11):4065-82. Preparation Read Literature 11.00-11.45 Lecture Title Mechanisms in pulmonary hypertension Instructor M.J.T.H. Goumans (Mol Cell Biology) Description Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasoproliferative disorder

characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis and plexiform lesions. Although the histomorphology of neointimal lesions is well described, the pathogenesis of PAH and neointimal development is largely unknown. After three decades of PAH pathobiology research the focus has shifted from vasoconstriction towards a mechanism of cancer-like angioproliferation. In this concept the role of disturbed blood flow is seen as an important trigger in the development of vascular remodeling. Still, questions remain about the exact role of these blood flow characteristics in disease progression. The current knowledge obtained from PAH animal models associated with disturbed pulmonary blood flow will be discussed and questions for future treatment strategies for PAH will be addressed.

Literature Dickinson Am J Physiol Lung Cell Mol Physiol. 2013 305(1):L1-14. Preparation Read literature 13.50-15.30 Workgroup Title Novel reporters in fibrosis Instructor M.J.T.H. Goumans (Mol Cell Biology) Description Novel reporters to assess tissue fibroses have recently become available. In this workshop you

will be challenged to think of how these commodities may be used to develop novel diagnostic and therapeutic strategies that can help in the clinical management of organ failure

Literature Preparation Thursday, October 16 Theme: Molecular Medicine 9.00-9.45 Lecture Title Diabetic nephropathy Instructor H. Baelde (Pathology) Description Diabetic nephropathy is the leading cause of end stage renal diseases worldwide. Even though

several diabetic animal models exist, not a single one develops renal changes sufficiently reflecting those seen in humans. This lecture provides an overview on animal models presenting with various features of diabetic nephropathy.

Literature Mouse models of diabetic nephropathy. Alpers CE1, Hudkins KL.Curr Opin Nephrol Hypertens. 2011 May;20(3):278-84

Preparation Read literature 10.00-10.45 Lecture Title Kidney fibrosis in experimental mouse models Instructor R.Bijkerk (Nephrology) Description Interstitial fibrosis in the kidney is one of the common findings in the pathology of chronic

kidney disease (CKD). Development of interstitial fibrosis is preceeded by a loss of the capillary network (rarefaction) in the kidney. These findings suggest an early, rate-limiting role for microvascular destabilization/loss in the pathogenesis of fibrosis. This lecture will discuss the use of lineage-tracing mouse models in which we can follow the cells of the vasculature to study the development of fibrosis.

Literature Selected review: Lineage-tracing methods and the kidney. Humphreys BD, Dirocco DP. Kidney Int. 2013.

Preparation Reading the literature 13.00-17.00 Self-study Title Blog update Instructor Assigned mentor

http://www.ncbi.nlm.nih.gov/pubmed/9403633

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Description Use this time to work on your blog and case report Friday, October 23 Theme: No program

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Week 9 Innovative therapeutic strategies

Clinical coordinators Atsma Topics LE Lecture Scientific coordinators van Zonneveld Concept of personalized medicine SS Self Study

Models for drug testing in CVD DE Demonstration Other teachers involved Mummery Cell therapy for failing hearts WO Workgroup

Vulto, Reinders Transplantation of islets to treat hyperglycemia PR Practical workEngels, Goumans, Atsma Approaches in gene therapy DB Debate

Monday Cell therapy and personalized medicine 127-oct

9.00-9.45 LE Islet TX Islet transplantation V4-46 Engelse9.45-10.00 Break

10.00-10.45 LE microfluidics Microfluidics to facilitate the development of personalized diagnostic or therapeutic strateg V4-50 Vulto10.45-11.00 Break11.00-12.00 LE MSC Mesenchymal stromal cells in kidney transplantation V4-50 Reinders12.00-13.30 Lunch13.30-15.30 SS Self study Self study for exam V4-50

Tuesday Cell therapy and personalized medicine 228-oct

11.00-11.45 LE Cell therapy Cell therapy for the heart, basic V4-46 Goumans11.45-12.00 Break12.00-12.45 LE Cell therapy Cell therapy for the heart, clinical V4-46 Atsma13.00-14.00 Lunch14.00-14.45 LE iPS Cardiomyocytes from Human Pluripotent Stem Cells : the new patient in Safety Pharmacolo V4-50 Mummery15.00-17.00 SS Writing a (short) blog Use this time to work on your blog V4-50

Wednesday Study study day29-oct

Thursday Study study day30-oct

Friday Exam Final knowledge test31-oct covering the total course

10.00-12.00 EX V4-46

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Week 9: Innovative therapeutic strategies

Coordinator(s): Atsma, van Zonneveld Teachers: Mummery, de Vries, Goumans, Engelse Outline The LUMC research theme ‘Vascular and regenerative medicine’ and the Einthoven Laboratory for Experimental Vascular Medicine is devoted to explore novel strategies for early diagnosis and therapy of patients with cardiovascular disorders. In this week we will highlight some of these novel approaches and discuss their potential clinical relevance. The aim of these lectures is to teach the students to differentiate between early, preclinical proof of principle studies and approaches that my find their way to the clinical arena. Topics

• Concept of personalized medicine • Models for drug testing in CVD • Cell therapy for failing hearts • Transplantation of islets to treat hyperglycemia • Approaches in gene therapy

Evaluation • Evaluation of blog contribution • Multiple choice exam week 9 • Evaluation of paper presentation

Day to Day program Monday, October 27 Theme: Cell therapy and personalized medicine 1 9.00-9.45 Lecture Title Islet transplantation Instructor M.A. Engelse (Nephrology) Description Transplantation of insulin-producing pancreatic islets in a specific population of people

suffering from (Type-I) diabetes has steadily gained momentum after publication of the “Edmonton Protocol” paper in 2000. Although isolation and purification of pancreatic islets from human cadaveric donor pancreas has become a standardized protocol, donor background and accompanying organ variability are major factors that determine isolation outcome. The islet transplantation world is currently involved in finding new ways to generate insulin producing beta cell mass from alternative sources like stem cells and other progenitors. In addition, bioengineering approaches are employed to create an optimal niche for islet transplantation.

Literature N Engl J Med. 2000 Jul 27;343(4):230-8.. Shapiro AM, et al Preparation Read the article 10.00-10.45 Lecture Title Microfluidics to facilitate the development of personalized therapeutic strategies Instructor P.Vulto (LACDR/Mimetas) Description Literature Preparation 11.00-11.45 Lecture Title MSCs in kidney transplantation Instructor M.E.J. Reinders (Nephrology) Description In recent years it has become clear that not only fibrotic repair but also restoration of damaged

kidney can occur and the use of cell therapy has been advanced as a means to activate endogenous repair mechanisms. In this perspective mesenchymal stromal cells (MSCs) are of particular interest. The immune-regulatory properties of MSCs in inflammatory models and diseases have highlighted their potential to reduce acute kidney injury and to prolong allograft survival after solid organ transplantation. Moreover, MSCs can also induce tissue regeneration


http://www.ncbi.nlm.nih.gov/pubmed?term=Shapiro%20AM%5BAuthor%5D&cauthor=true&cauthor_uid=10911004

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and repair due to their anti-fibrotic and angiogenic properties. In this lecture the latest insight and the current clinical status in patients after renal transplantation will be described.

Literature - Alagesan and Griffin 2014. Cur Opinion Organ Transpl. Autologous and allogeneic MSCs in organ transplantation: what do we know about their safety and efficacy. - Mesenchymal stromal cells to prevent fibrosis in kidney transplantation. ReindersME, deFijterJW, Rabelink TJ. Curr Opin Organ Transplant. 2014 Feb;19(1):54-9. Review.

Preparation Reading of the literature 13.00-17.00 Self-study Title Self-study for exam Tuesday, October 28 Theme: Cell therapy and personalized medicine 1 11.00-11.45 Lecture Title Cells therapy for the heart: pre-clinical Instructors M.J.T.H. Goumans (Molecular cell biology) Description It has been over a decade since the concept of cell-based therapy was coined as a method to

treat patients who suffered the consequences of myocardial infarction (MI). Shortly after promising preclinical results emerged, a rapid translation to the clinic was made using stem cells isolated from a variety of sources, including bone marrow mononuclear cells (BM-MNCs), mesenchymal stem cells (MSCs) and cardiac progenitor cells (CPCs). The hypothesis was that transplanted stem cells would provide cues that enhance the wound healing process and locally differentiate into new contractile cardiac tissue. However, although the clinical trials have been shown to be safe, only a relatively small effect on cardiac function has been observed. It has become clear that each cell type applied in cell-based therapy has its own ability for cardiac repair. The basic knowledge of each cell population’s behaviour and its ability to interfere in different stages of post-MI wound healing will be discussed.

Literature Heart. 2014 Aug 1;100(15):1153-1157 Preparation Reading the literature 12.00-12.45 Lecture Title Cell therapy Instructors D.E. Atsma (Cardiology) Description Cell therapy for the heart: clinical. In the last decade clinical cell therapy for cardiac disease

has moved from Phase I/II to Phase III trials. Despite the fact that overall success is claimed for this novel treatment modality, the results seem contradictory at times, which might be attributable to differences in patient population, cell type, administration routes, etc. We will discuss the pitfalls and challenges in clinical cell therapy trials, as well as the results that have been obtained so far. Also, future directions for clinical trials are highlighted.

Literature Selected state of the art papers will be handed out Preparation Reading the literature. 14.00-14.45 Lecture Title Cardiomyocytes from Human Pluripotent Stem Cells : the new patient in Safety

Pharmacology, Drug Discovery and Disease Instructor C.L. Mummery (Anatomy and embryology) Description Derivation of heart cells from human pluripotent stem cells (hPSC) is an area of growing

interest as a way of modelling disease phenotypes and as a platform for drug discovery and toxicity. Applying the underlying developmental mechanisms that control cardiac differentiation to hPSCs through the use of defined culture conditions in vitro is rapidly moving the field forward. We are now using this technology to select the progenitors of cardiomyocytes, endothelial cells and smooth muscle cells. Applications of hESC- and hiPSC-derived cardiomyocytes in drug discovery, disease and safety pharmacology will be shown. The field potential of hPSC-CM can be measured using commercially available multi electrode arrays. Systematic generation of dose response curves for cardiac and non-cardiac drugs show

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that hPSC-CM accurately predict reported drug effects on the human heart. Also, induced pluripotent stem cells (hiPSC) from patients with genetic disease are source of somatic cells that can carry disease mutations and show disease phenotypes.

Literature Bellin M, Marchiotti C, Gage F, Mummery CL. Induced pluripotent stem cells: the new patient? Nat Rev Mol Cell Biol., 2012. 13(11):713-26

Preparation Read literature Wednesday, October 29 Theme: Study Thursday, October 30 Theme: Study Friday, October 31 Theme: Exam 11.00-12.00 Exam Title Knowledge test 2 Description Covering week 1-9



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Week 10 Case Report

Clinical coordinators Atsma Topics LE Lecture Scientific coordinators van Zonneveld Write case report SS Self Study

Implement all knowlegde aquired and blogged i DE Demonstration Other teachers involved WO Workgroup

PR Practical workDB Debate

Monday Write case report3-nov

Tuesday Write case report4-nov

Wednesday Write case report5-nov

Thursday Submit case report6-nov

Friday Presentations case reports7-nov

12.00 - 15.00 WO Case reports Presentation Case Reports 1-2 V2-3415.00 - 15.15 Break15.15 - 16.15 WO Case Reports Presentation Case Reports 3-4 V2-3416.15-17.00 End Drinks

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Week 10: Case report

Coordinator(s): Atsma, van Zonneveld, de Bruin Teachers: Outline Based on the detailed case description and the accumulated information in the students blogs the student use most of the time in these final week to write a case report. These reports are virtually manuscripts for papers that not only include the anamnesis, laboratory tests and the diagnosis of the particular patients but also outline aspects of the etiology and the pathophysiology and a proposal of a therapeutic plan and whether there is an outlook to future therapeutic strategies. The dedicated mentors of the students will be available for advice in preparing the manuscript. The report is an important part of the students examination. Learning objectives

• Determine the pathogenic mechanism(s) that might underlie the complaints of a patient diagnosed with a cardiovascular disorder

• Create a diagnostic plan by evaluation of laboratory tests that could be applied based on a differential diagnosis and motivate why this technique is appropriate to be able to diagnose correctly

• Develop a therapeutic plan based on the results from diagnostic tests and corresponding diagnosis and describe the method to check the effect of the intervention

• Understand the molecular mechanisms underlying innovative therapeutic strategies and relevant experimental animal models

Evaluation

• During the 10 weeks of the half-minor, time is scheduled to work on your blog. • The 10th week is completely dedicated for this purpose as well. • The case-report has to be written in English. • Part of your blog can be used as the basis for your case-report and therefore, keeping good (digital)

notes during the entire module is highly recommended as this will help you to write your case-report. The case-report has to be finished and uploaded to blackboard on Wednesday November 5th 24.00 hour. Your case-report will be graded by the block-coordinators (grade 1-10). In case of a case-report which is of insufficient quality, the student will have to revise the report after being contacted by one of the block-coordinators to discuss any questions/problems.

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Appendix 1 – Assessment form Half Minor Heart and Bloodvessels

Name student:

Student number:

Date:

Assignment Qualification Mark Weight Final

Workgroups Paper presentation week 2 p/f

Paper presentation week 4 p/f




Knowledge test week 1-3 Written exam 1 1-10 0.125

Knowledge test week 1-6 Written exam 2 1-10 0.125

Final knowledge test week 1-9

Written exam 3 1-10 0.25

Cumulative blog Written reflections throughout the half minor

p/f

Case Report Written case report 1-10 0.50

Total

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Appendix 2: Guidelines Case report Use these guidelines to write your case-report. Listed are topics that you can implement in your case-report. Length of the report should be around 3000-4000 words

• Title

• Abstract (max 200 words)

• Case-description o Medical History o Most important laboratory test results of the past/present, and interpretation of these results o Description of the current state of disease / comorbidities o Diagnosis/summary

• Epidemiology

o Global & national epidemiology description o Cultural/ethnic differences o Healthcare costs associated with the disease

• Pathogenesis

o Underlying mechanistic insight (both pathophysiology as well as the molecular mechanisms) o Previous knowledge, current knowledge and in particular new emerging insights/contributors

to disease o Risk factors: Are these of predictive value? How are these contributing to the disease

state/development? o Co-morbidity of other pathophysiology? Which should we be aware of?

• Diagnosis

o What diagnostic tools are currently available? Are these sufficient? What are the pitfalls? What extra information do you need? And why? How to interpret the results of the diagnostics done?

o What diagnostic tools that might be available in the future? What are the pros/cons of these? What is their added value?

o Are the results (either from current or future diagnostics) of prognostic value?

• Current therapies o What are the current guidelines to treat this patient? o What are the therapeutic options? (drug, versus non-drug/lifestyle) o Are there side-effects/complications/restrictions/limitations? o What are the associated costs? o Are they contributing to the quality of life? o Do we need more insight in the pathogenesis of the disease?

• Future/innovative therapies

o Describe the possible next generation therapeutics o What is the most ideal therapeutic option? (even if it is not yet possible?). o What are the pros/cons? o Are they contributing to quality of life? o What are the considerations regarding the price of these innovative therapies? o What is the prognosis of the patient? o Do the next generation therapies contribute to the prognosis as compared to standard

therapies?

• Summary & Conclusion o Summarize the case-report in a clear conclusion paragraph

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Appendix 3: Guidelines Case report score

Case report: about 6 pages, covering a discussion about the (im)possibilities to treat the patient, now and in the near future. This report contains a comparison of at least 5 relevant articles, including a discussion about the significance of the analysed data, validity of the conclusions, potential confounders and biases. Choices regarding the patient are supported by critically appraised articles. Pass Good Excellent Description of patient case I

Description of patient case by means of relevant data. Data are not necessarily described in coherence. All relevant data are included: chief complaint, history of present illness, past medical history, family history, social history, physical examination.

Description of patient case by means of relevant data, which are presented in coherence. If relevant, some attention is spent on the context (psychosocial, economic etc.) of the patient.

In depth description of patient case by means of relevant data, discussing their mutual influence.

Description of the patient case II (interpretation and follow up) & relevance

Description of the patient case after first interpretation of the data: diagnoses, lab research, treatment policy. Again: the issues are not really discussed in coherence. Relevance of patient case is not really discussed.

Coherent description of the patient case after first interpretation of the data: diagnoses, lab research, treatment policy are related. Relevance of the case is circumscribed.

The relevance of this particular patient case is described in relation to a clinical (diagnoses, diagnostic follow up and treatment), basic science or contextual issues. Relevance of this case is illuminated in a convincing way.

Interdisciplinary approach

Data remain on clinical level. Patient problem is understandable. Case description is followed by explanation of some aspects of underlying mechanisms.

Discussion of patient data takes different clinical and basic science disciplines into account. Some of these viewpoints are linked. Pathogeneses and epidemiological viewpoints are discussed and related to research question.

Patient data are presented from different clinical disciplines and related to relevant anatomical, pathophysiological and biochemical issues. Pathogeneses and epidemiological viewpoints are intertwined in the description and choice of presented patient data.

Methods/Data gathering/Management outcome

Description of choice of articles, articles are relevant for patient case.

Description of choice of articles. All relevant topics are included by this choice of articles. Well chosen references regarding patient problem.

Description of choice of articles, and relevance for chosen studies for the case study. Well chosen articles, including a review and/or very recent studies by opinion leaders of the field.

Therapeutic treatment Clinical management is based on and explained by a few supporting articles.

Clinical management is based on articles which convincingly support the proposed management and are critically discussed where appropriate. In management, the complexity of the patient case and its inherent risk factors are taken into account.

Clinical management is based on articles which convincingly support the proposed management. In management, the complexity of the patient case (including social-economic, psychological, cultural and gender issues) and its inherent risk factors are taken into account. Critical appraisal of the guidelines, which should be applied in this particular patient case.

Innovation Identification of some innovative therapies which might be relevant for the patient. Explanation in which respects they are relevant.

Discussion of the most relevant and innovative therapies for this particular patient case. These are discussed from the perspective of relating underlying mechanisms and

In depth discussion of the most relevant and innovative therapies for this particular patient case. These are discussed from the perspective of relating underlying mechanisms and clinical

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clinical symptoms and explicitly related to the patient case.

symptoms and reason future developments by balancing out innovative therapies. Explicit linking with patient case.

Discussion: scientific debate

The student displays critical behavior to some parts of the conclusions, innovations or methodology of some studies.

A concise appraisal of these therapies, e.g. the studies and used methodologies which are supposed to evidence these therapies. The discussion encompasses a new viewpoint or other literature to shed another light on the current debate about the innovations.

An analysis of strong and weak points of the described innovations and the studies that aim to evidence them. Other sources or perspectives are used to illuminate new directions in current or future research. Future developments and links to alternative approaches and outcomes are convincingly pointed out by using other literature. Consequences for this particular patient cases are also discussed.

Conveying knowledge Core concepts are explained, overall argumentation is understandable, at some points, steps in argumentation are not completely clear.

Core concepts are explained, argumentation is easy to follow. Overall, steps in argumentation are clear, most theoretical concepts are related to patient case.

All relevant concepts are explained in relation to patient case, argumentation is completely clear and convincing.

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