PATH310_M02_onQ_CompanionGuide

MODULE 02 CARDIOVASCULAR DISORDERS Please note: This course was designed to be interacted and engaged with using the online modules. This Module Companion Guide is a resource created to complement the online slides. If there is a discrepancy between this guide and the online module, please refer to the module. How can you help protect the integrity and quality of your Queen’s University course? Do not distribute this Module Companion Guide to any students who are not enrolled in P ATH 310 as it is a direct violation of the Academic Integrity Policy of Queen’s University. Students found in violation can face sanctions. For more information, please visit https://www.queensu.ca/academic- calendar/health-sciences/bhsc/ . PATH 310 INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE

MODULE 02 COMPANION GUIDE PATH 310 INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 2 TABLE OF CONTENTS INTRODUCTION ..................................................................................................................................................... 6 Introduction ot Module 02, Cardiovascular Disorders ................................................................................. 6 Learning Outcomes ........................................................................................................................................... 6 Module Assessments ........................................................................................................................................ 6 Team-Based Learning Assignment #1 ........................................................................................................ 7 Course Icons ...................................................................................................................................................... 7 Module Outline .................................................................................................................................................. 7 SECTION 01: Atherosclerosis ................................................................................................................................ 9 Case Presentation: Mr. Jones ........................................................................................................................... 9 Autopsy Report: Abnormalities in the Heart .................................................................................................. 9 Autopsy Report: Muscular Wall Rupture ...................................................................................................... 10 Autopsy Report: Gross Anatomy of the Heart ............................................................................................. 11 Autopsy Report: Locations of Blockages ...................................................................................................... 12 Question – Normal Blood Vessels ................................................................................................................. 13 Question – Arteries and Veins ....................................................................................................................... 13 Question – Potential Causes of Blockages ................................................................................................... 14 Risk Factors for Atherosclerosis .................................................................................................................... 14 Question – Mr. Jones’ Risk Factors ................................................................................................................ 15 Mr. Jones’ Probable Cause of Death .............................................................................................................. 16 Atherosclerosis: The Scope of the Problem ................................................................................................. 17 Characteristics of an Atheromatous Plaque ................................................................................................ 17 Response-to-Injury Hypothesis ..................................................................................................................... 18 Fatty Streaks ................................................................................................................................................ 19 Fibrofatty Atheroma ................................................................................................................................... 20 Question – Response-to-Injury Hypothesis .................................................................................................. 20 Stable and Vulnerable Plaques ...................................................................................................................... 21 The Natural Progression of Atherosclerosis ................................................................................................ 21 Development of an Atherosclerotic Plaque and Clinical Presentation ..................................................... 22 Progression of Aortic Atherosclerosis ...................................................................................................... 23 Autopsy Report: Occlusion by Thrombus ..................................................................................................... 24 Autopsy Report: Right Coronary Artery ........................................................................................................ 24 Mr. Jones’ Case: Occlusive Thrombosis Causes Acute Myocardial Infraction .......................................... 26

MODULE 02 COMPANION GUIDE PATH 310 INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 3 Autopsy Report: Histology of Heart Muscle ................................................................................................. 26 Mr. Jones’ Cause of Death .............................................................................................................................. 26 Question – Location of Plaques and Occlusions ......................................................................................... 27 Culprits for Endothelial Dysfunction: Hemodynamic Forces ..................................................................... 28 Types of Blood Flow ........................................................................................................................................ 28 Turbulent Blood Flow and atherosclerosis .................................................................................................. 29 Question – Location of Atherosclerotic Lesions .......................................................................................... 30 Feedback: Localization of Atherosclerosis Lesions ..................................................................................... 30 Shear Stress, Endothelial Dysfunction, and Atherosclerosis ..................................................................... 31 Effect of Shear Stress on Endothelial Cell Phenotype ................................................................................. 31 Shear Stress and Key Regulator Genes of Inflammation ........................................................................... 32 Shear Stress and Master Regulator Genes .................................................................................................. 32 Question – The Effect of Shear Stress on Endothelial Phenotype ............................................................. 32 Feedback: The Effect of Shear Stress on Endothelial Phenotypes ............................................................ 34 Case Presentation: Mr Jones’ Son .................................................................................................................. 35 Question – Mr. Jones’ Risk Factors ................................................................................................................ 36 Culprits for Endothelial Dysfunction: Hyperlipidemia ................................................................................ 37 Review of Lipoproteins ............................................................................................................................... 38 Reverse Cholesterol Transport ...................................................................................................................... 39 The Importance of H D L in Reverse Cholesterol Transport ......................................................................... 39 Role of Fats in Atherosclerosis ....................................................................................................................... 40 Role of Fats in Atherosclerosis: Mr. Jones’ Son’s Blood ............................................................................... 40 Plasma Lipid Levels and Associated Health Risks ....................................................................................... 41 Question – T C/H D L Ratio ................................................................................................................................. 42 Question – “Good” vs “Bad” Cholesterol ....................................................................................................... 43 “Good” vs “bad” Cholesterol ........................................................................................................................... 43 Types of hyperlipidemia ................................................................................................................................. 44 Primary Hyperlipidemia .................................................................................................................................. 44 Using GW A S to Identify Genes Linked to Coronary Artery Disease ....................................................... 45 Question – Identifying the Type of Hyperlipidemia ..................................................................................... 46 Question – Familial Hypercholesterolemia .................................................................................................. 46 Feedback: Familial Hypercholesterolemia ................................................................................................... 46 Question – Dietary Sources of Cholesterol .................................................................................................. 48

MODULE 02 COMPANION GUIDE PATH 310 INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 4 Dietary Sources of H D L and L DL ..................................................................................................................... 48 Treatment Approaches for Hyperlipidemia ................................................................................................. 49 The Way Forward for Mr. Jones’ Son ............................................................................................................. 49 Hear From the Experts – Atherosclerosis ..................................................................................................... 50 Section 01: Summary – Atherosclerosis ....................................................................................................... 50 SECTION 02: Channelopathies ........................................................................................................................... 51 Case Presentation: Benjamin ......................................................................................................................... 51 Benjamin’s Autopsy Report ............................................................................................................................ 51 Benajmin’s Family History .............................................................................................................................. 52 Question – Benjamin’s Cause of Death ........................................................................................................ 52 Sudden Cardiac Death .................................................................................................................................... 52 Sudden Death by Pulmonary Thromboembolism .................................................................................. 53 Sudeen Death by Severe Stenosis ............................................................................................................. 53 Question – Benjamin’s Case ........................................................................................................................... 54 Molecular Autopsies and Medical Investigations ........................................................................................ 54 Inheritable Cardiovascular Diseases ............................................................................................................. 55 The Cardiac Action Potential and Channelopathies .................................................................................... 56 Prevalence of Channelopathies ..................................................................................................................... 56 Pathophysiology of Channelopathies in Relation to LQTS ......................................................................... 57 Different Types of L Q T S .................................................................................................................................. 58 Genes Associated with L Q T S .......................................................................................................................... 58 Question – Discovering Genes Associated with L Q T S ................................................................................. 59 Influence of Genetic Information on Our Understanding of Channelopathies ....................................... 59 Understanding Locus and Clinical Heterogeneity ....................................................................................... 60 Question – How Do We Approach Genetic Testing? ................................................................................... 61 How Do We Assess the Association Bewtween Changes in a Gene and Particular Disease? ................ 61 Genes Associated With L Q T S .......................................................................................................................... 62 Question – Additional Considerations of Genetic Testing .......................................................................... 63 Feedback: Additional Considerations of Genetic Testing ........................................................................... 63 Clinical Presentations Associated with L Q T S Genes .................................................................................... 64 Question – Determining Benjamin’s Diagnosis ........................................................................................... 66 Benjamin’s Case: Genetic Testing Results and Implications for His Family .............................................. 66 Testing Tianna for L Q T S .................................................................................................................................. 67

MODULE 02 COMPANION GUIDE PATH 310 INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 5 Penetrance and Expressivity .......................................................................................................................... 67 100% Penetrance and Constant Expressivity .......................................................................................... 68 <100% Penetrance and Constant Expressivity ........................................................................................ 68 < 100% Penetrance and Variable Expressivity ......................................................................................... 69 Activity – Hypothetical Scenario on Penetrance and Expressivity ............................................................. 69 Question – Penetrance and Expressivity ...................................................................................................... 70 Incorporating Penetrance and Expressivity into Clinical Interpretation of Tianna’s Tes ting Results .... 71 Genetic Purgatory and Channelopathies ..................................................................................................... 71 How Geneticists Interpret Variant Data for the Patient ............................................................................. 72 Challenges of Clinical Interpretation of Genomic Variants in Channelopathies ...................................... 72 LQ T S Risk Stratification ................................................................................................................................... 73 Question – What are the Next Steps for Tianna? ........................................................................................ 74 Quesiton – Managing Tianna’s L Q T S .............................................................................................................. 74 Managing Arrhythmias in Channelopathies ................................................................................................ 75 The Way Forward for Benjamin’s Family ...................................................................................................... 75 Hear from the Experts – Channelopathies ................................................................................................... 76 Section 02: Summary – Channelopathies ..................................................................................................... 76 CONCLUSION ....................................................................................................................................................... 77 Question – Integrate Your Knowledge .......................................................................................................... 77 Learning Outcomes ......................................................................................................................................... 77 Acknowledgements ......................................................................................................................................... 77 Module 02 Complete! ..................................................................................................................................... 78