PATH 310 Module 02 Companion Guide PDF

PATH 310 oiw INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE 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...

PATH 310 oiw INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE 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 PATH 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/. MODULE 02 COMPANION GUIDE PATH 310 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 INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 2 MODULE 02 COMPANION GUIDE PATH 310 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 HDL 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 – TC/HDL Ratio.................................................................................................................................42 Question – “Good” vs “Bad” Cholesterol.......................................................................................................43 “Good” vs “bad” Cholesterol...........................................................................................................................43 Types of hyperlipidemia.................................................................................................................................44 Primary Hyperlipidemia..................................................................................................................................44 Using GWAS 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 INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 3 MODULE 02 COMPANION GUIDE PATH 310 Dietary Sources of HDL and LDL.....................................................................................................................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...........................................................................................................................52 Case Presentation: Benjamin.........................................................................................................................52 Benjamin’s Autopsy Report............................................................................................................................52 Benajmin’s Family History..............................................................................................................................53 Question – Benjamin’s Cause of Death........................................................................................................53 Sudden Cardiac Death....................................................................................................................................53 Sudden Death by Pulmonary Thromboembolism..................................................................................54 Sudeen Death by Severe Stenosis.............................................................................................................54 Question – Benjamin’s Case...........................................................................................................................55 Molecular Autopsies and Medical Investigations........................................................................................55 Inheritable Cardiovascular Diseases.............................................................................................................56 The Cardiac Action Potential and Channelopathies....................................................................................57 Prevalence of Channelopathies.....................................................................................................................57 Pathophysiology of Channelopathies in Relation to LQTS.........................................................................58 Different Types of LQTS..................................................................................................................................59 Genes Associated with LQTS..........................................................................................................................59 Question – Discovering Genes Associated with LQTS.................................................................................60 Influence of Genetic Information on Our Understanding of Channelopathies.......................................60 Understanding Locus and Clinical Heterogeneity.......................................................................................61 Question – How Do We Approach Genetic Testing?...................................................................................62 How Do We Assess the Association Bewtween Changes in a Gene and Particular Disease?................62 Genes Associated With LQTS..........................................................................................................................63 Question – Additional Considerations of Genetic Testing..........................................................................64 Feedback: Additional Considerations of Genetic Testing...........................................................................64 Clinical Presentations Associated with LQTS Genes....................................................................................65 Question – Determining Benjamin’s Diagnosis...........................................................................................67 Benjamin’s Case: Genetic Testing Results and Implications for His Family..............................................67 Testing Tianna for LQTS..................................................................................................................................68 INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 4 MODULE 02 COMPANION GUIDE PATH 310 Penetrance and Expressivity..........................................................................................................................68 100% Penetrance and Constant Expressivity..........................................................................................69 WOMEN Generally the incidence increases as we age, but men are 2x more likely to have a heart attack (myocardial infarction; MI) than women. CORONARY ARTERIES Atherosclerosis is common among the coronary arteries, which may lead to angina (chest pains), CAD, myocardial infarctions or death from cardiac arrest (sudden stopping of the heart). You will learn why the coronary circulation is vulnerable to atherosclerosis in the upcoming slides. CHARACTERISTICS OF AN ATHEROMATOUS PLAQUE This content was retrieved from Seciton 01 Slide 14 of 58 of the online learning module It is necessary to identify the characteristics of a plaque before diving into the pathophysiology of atherosclerosis. The characteristics that contribute to plaque formation include: Endothelial dysfunction Vascular inflammation Build up of lipids, cholesterol, calcium, and cellular debris You will learn about how each of these factors contribute to atherosclerosis later in this module. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 17 MODULE 02 COMPANION GUIDE PATH 310 RESPONSE-TO-INJURY HYPOTHESIS This content was retrieved from Section 01 Slide 15 of 58 of the online learning module The contemporary theory of the pathology of atherosclerosis is called the response-to-injury hypothesis. According to this theory, atherosclerosis develops as a healing response to endothelial injury. Hence, endothelial dysfunction is a critical triggering event. Learn about the sequence of events described by the response-to-injury hypothesis from Dr. Manduch. When prompted drag the slider. (03:17) Start of Audio Transcript: We will begin exploring the response to injury hypothesis by dragging the slider to the first step, which is endothelial injury. Recall that endothelial cells line the inner surface of all vessels and are in direct contact with flowing blood. Endothelial cell injury may be caused by a number of stimuli, including hemodynamic forces, hyperlipidemia, hypertension, smoking, toxins, and viruses. Once damaged, endothelial cells become dysfunctional, which may lead to increased vascular permeability, leukocyte adhesion, and thrombosis. Drag the slider to the second step so we can look at the accumulation of lipoproteins and macrophages. Once endothelial cell damage or dysfunction has occurred and the blood vessel permeability is increased, there will be many things coming into the intima of the blood vessel from the blood. For example, low-density lipoproteins, LDLs, and very low-density lipoproteins, VLDLs, will get oxidized. Monocytes also transform into macrophages in this step. This change is mediated by a receptor on the dysfunctional endothelial cells that allows monocytes to enter the tunica intima where they will transform. Now drag the slider to the third step so we can explore the role of smooth muscle cells and foam cells. Smooth muscle cells, or SMC, in the tunica media migrate into the tunica intima. The smooth muscle cells, along with the macrophages, begin to engulf the oxidized LDLs to form foam cells. The disease progresses and creates what's called an atherosclerotic cap. Drag the slider now to the fourth step where fatty streaks have now formed. This is the first visual manifestation of atherosclerosis, and it is at this point where it is still reversible. You can get rid of these streaks with behaviour and diet modification since they are the result of fat accumulation and foam cells in the endothelial lining. Finally, drag the slider to the fifth step, where a complete plaque has formed. This final step is irreversible, and the structure formed now is called an atheromatous plaque or fibrofatty atheroma or just plaque. There is progressive lipid accumulation within the tunica intima, and the growing number of molecules and substances that accumulate form this atheromatous plaque, which, when fully formed, will have a necrotic centre and a fibrous cap. Note the additional information revealed in step 5. 1. Injury 2. Accumulation INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 18 MODULE 02 COMPANION GUIDE PATH 310 3. Smooth Muscle Cells 4. Fatty Streaks 5. Complete Plaque Examine the two final stages of atherosclerosis, fatty streaks and plaque, in more detail - Refer to Page 19 – 20 Reference: Kumar, V., Abbas, A., Aster, J. (2015). Robbins & Cotran Pathologic Basis of Disease Ninth Edition (pp. 495). Saunders. FATTY STREAKS Subpage of Section 01 Slide 15 of 58 – Examine the two final stages of atherosclerosis, fatty streaks and plaque, in more detail 1/2 Fatty streaks are the first visual manifestation of atherosclerosis and is the point at which atherosclerosis is reversible through behavioural and diet modification. Fatty streaks are the accumulation of fat and foam cells that are visible if you look through the endothelial lining into the lumen of a vessel. Fat appears as a slightly darker yellow in colour and foam cells can be yellow if they take up fat. Staining with sudan red can help enhance the visibility of adipose tissue. Compare the appearance of fatty streaks with and without sudan red staining. STAINED FATTY STREAKS In this image, the vessel branch points, also known as ostia, are the empty, white spaces. The flow of blood follows the direction of the dashed arrow and is hitting the area of the branch point, triggering the accumulation of fat and the formation of atherosclerosis. The stain used to identify sites of fat accumulation acts on fat cells, which helps us locate fatty streaks. UNSTAINED FATTY STREAKS This is an image of the abdominal aorta cut longitudinally down the length of the vessel and opened like a book. The arrows point to fatty streaks, which again, are typically found near the ostia of branching vessels. Without staining fatty streaks appear as a slightly darker yellow. You will come to understand why the ostia of branching points are common sites for atherosclerosis later in this section. References: Kumar, V. Abbas, A. Aster, J. (2015). Robbins & Cotran Pathologic Basis of Disease Ninth Edition (pp. 497). Saunders. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 19 MODULE 02 COMPANION GUIDE PATH 310 Kumar, V. Abbas, A. Aster, J. (2015). Robbins & Cotran Pathologic Basis of Disease Ninth Edition (pp. 588). Saunders. FIBROFATTY ATHEROMA Subpage of Subpage of Section 01 Slide 15 of 58 – Examine the two final stages of atherosclerosis, fatty streaks and plaque, in more detail 2/2 The photograph presented shows a cross-sectioned vessel containing a fibrofatty atheroma (plaque). The fibrofatty plaque has grown to occlude a large portion of the vessel lumen. It occupies the space of the tunica intima, which is now known as the neo-intima, as it is the new thickened layer of intima. Reference: Image courtesy of Dr. Marosh Manduch. QUESTION – RESPONSE-TO-INJURY HYPOTHESIS This content was retrieved from Section 01 Slide 16 of 58 of the online learning module Using your knowledge about the pathophysiology of atherosclerosis, answer the question. Question: Which of the following does not play a role in the response-to-injury hypothesis linked to atherosclerosis? a) Chronic endothelial injury resulting in endothelial dysfunction and increased permeability. b) Enhanced accumulation of lipids both within the cells (macrophages and smooth muscle cells) and proteoglycans. c) Modification of lesional lipoproteins by oxidation. d) Proliferation of smooth muscle cells in the media leading to expansion of the muscle wall. Feedback: INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 20 MODULE 02 COMPANION GUIDE PATH 310 The correct response is d) Proliferation of SMCs does not occur in the media. According to the response-to-injury hypothesis, this step occurs in the intima. STABLE AND VULNERABLE PLAQUES This content was retrieved from Section 01 Slide 17 of 58 of the online learning module The atheromatous plaque is clinically stable and not thrombosis-prone. However, it can progress into a structurally vulnerable (unstable) plaque that is prone to complications, leading to thrombosis. Examine the differences between the stable and vulnerable plaques in the illustration; then, view equivalent histological images. Notice the thicker fibrous cap in the stable plaque. Schematic Histology Reference: Schematic & Histology: Kumar, V., Abbas, A., Aster, J. (2015). Robbins & Cotran Pathologic Basis of Disease Ninth Edition (pp. 498-500). Saunders. THE NATURAL PROGRESSION OF ATHEROSCLEROSIS This content was retrieved from Section 18 of 58 of the online learning module In examining Mr. Jones’ arteries, the pathologist found several blockages along his coronary arteries. This finding is significant, as a reduction in lumen diameter along the main vessels that supply blood to the heart can result in oxygen deprivation and tissue damage. For documentation, the extent of the other blockages was recorded. Listen to Dr. Manduch briefly describe the natural progression of atherosclerosis. (04:46) View the audio transcript. Start of Audio Transcript: The preclinical phase of atherosclerosis usually occurs at a young age, and the patients aren't even aware that it is happening mostly because there are no symptoms, so they feel absolutely fine. And this creates an issue for the family doctor or medical professional to get the patient to modify or adjust their behaviour when they feel that they're perfectly healthy. From a normal artery, we have the progression, as we discussed, through a potential sort of fatty streak, the development of fibrofatty plaque, which can then become either advanced or vulnerable plaque. Then we cross -- or at this point, we cross into the clinical phase, which usually happens by middle age, such as mid- 40s or even later, and it is at this point that patients start getting symptoms. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 21 MODULE 02 COMPANION GUIDE PATH 310 So what are these symptoms? The earliest symptom to understand is what happens when a patient develops critical stenosis. So nothing really happens other than, gradually over time, the plaque grows and starts to occlude the vessel. So for example, the plaque could occlude 50% of the artery, then there is 50% less blood flow able to go through that artery and supply the heart. But the patient is still able to manage and cope and do something that they need to do, and so there are no symptoms. However, once the occlusion goes to about 75% or more, that's called critical stenosis. And so 75% is the threshold where, if you need more oxygen, that the blood that can fit through that stenosed artery is able to deliver, you will then, or the patient will then start to get symptoms, and these symptoms are usually chest pain. So two other clinical presentations involve an acute or sudden change in the plaque itself. In this example, most commonly, you get a thrombus that is superimposed on top of the established plaque within the artery, or lumen of the artery. For example, with a plaque, it could be 70% occluded, and everything is fine. There are no symptoms. But then there's an acute change, and you could get another thrombus or a clot on top of that resulting in, let's say, an 85 to 90% occlusion. And now that's not enough, so now you do get symptoms. And this occlusion now, or change in the plaque, can be caused by plaque rupture where the thin fibrous cap can break. There can be an erosion of the plaque. You can get plaque hemorrhage where plaque gets inside the pre-existing plaque and expands it, or you can get thrombi formation within the walls of the vessel or even an embolization that lodges in another area downstream of the thrombus formation. Alternatively, in rare cases, you can get an aneurysm, which is a ballooning of the arterial wall. That's the aneurysm, and the aneurysm, when it gets big enough, it can actually rupture. If the blood escapes, the patient will be in life-threatening danger, and this can occur because the smooth muscle cells are, as you recall, they're sort of exiting the media and entering the intima where they're making that plaque. So the wall of the artery, which is really the thick portion of the artery, the muscular portion is the media, and that portion of the artery gets thinner and thinner until the pressure of the blood that's flowing through it sort of push on it and make this balloon or aneurysm that then may eventually rupture. End of Audio Transcript. Reference: Adapted from images from Servier Medical Art. Servier Medical Art. (n.d.). Arteries - Atherothrombosis. Retrieved 1 May 2020, from https://smart.servier.com/image-set-download/ DEVELOPMENT OF AN ATHEROSCLEROTIC PLAQUE AND CLINICAL PRESENTATION This content was retrieved from Section 01 Slide 19 of 58 of the online learning module As you can now appreciate, after the initial development of an atherosclerotic plaque, if the general conditions that gave rise to the initial plaque do not change significantly, the plaque progresses and can lead to significant abnormal physiological effects and clinical symptoms. Review atherosclerotic plaque progression and how Mr. Jones could have conceivably developed his atherosclerotic condition. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 22 MODULE 02 COMPANION GUIDE PATH 310 Early Lesion The first step involves injury to the endothelium. This step is asymptomatic, so Mr. Jones would not have realized he was developing atherosclerotic disease. Plaque Growth The gradual growth of a plaque damages the inner wall of an artery. Over time, fatty deposits composed of cholesterol and other cellular products also build up at the site of injury, narrowing the arteries. Mr. Jones’ risk factors, especially hyperlipidemia, increased the likelihood of this step occurring. Plaque Rupture Eventually, the thin fibrous cap of the plaque could have ruptured, spilling cholesterol and other cellular substances into the bloodstream. Blood Clot Formation The rupturing of the plaque may cause the formation of a blood clot. This can block blood flow to a specific part of the body. As seen in Mr. Jones’ autopsy report, it appears blood flow was significantly blocked from reaching his heart. For interest, learn how atherosclerosis progression can be visualized post-mortem - Refer to Pages 23-24 Reference: Mayo Clinic. (April 24, 2018) Arteriosclerosis / atherosclerosis. Retrieved June 19 2020, from https://www.mayoclinic.org/diseases-conditions/arteriosclerosis-atherosclerosis/symptoms- causes/syc-20350569 PROGRESSION OF AORTIC ATHEROSCLEROSIS Subpage of Section 01 Slide 19 of 58 – Learn how atherosclerosis progression can be visualized post-mortem 1/1 A common site to inspect for signs of atherosclerosis post-mortem is the thoracic or abdominal aorta. Listen to Dr. Manduch discuss features of aortic atherosclerosis progression (01:05) Start of Audio Transcript: Here are three examples of abdominal aortas from actual patients, and they show us examples from mild atherosclerosis on the left to moderate atherosclerosis in the middle and advanced atherosclerosis on the right side. In the mild atherosclerosis case, we have some raised irregularities, some yellow fat or yellow streaks, whereas in the advanced stage, you can see crusting and ulceration of the plaques. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 23 MODULE 02 COMPANION GUIDE PATH 310 There's a lot of calcium in there that forms and makes the plaque brittle. And so these are the advanced or complicated plaques, and these are the ones that can cause serious complications for patients by sort of rupturing or even sort of causing mural thromboses. End of Audio Transcript. Reference: Images courtesy of Dr. Marosh Manduch. AUTOPSY REPORT: OCCLUSION BY THROMBUS This content was retrieved from Section 01 Slide 20 of 58 of the online learning module As part of Mr. Jones’ autopsy report, some histological cross sections of his coronary arteries were examined. As you can now appreciate, there is evidence of very thin fibrous caps which resulted in plaque rupture and subsequent complete occlusion of this portion of the coronary artery. Reference: Kumar, V., Abbas, A., Aster, J. (2015). Robbins & Cotran Pathologic Basis of Disease Ninth Edition (pp. 499). Saunders. AUTOPSY REPORT: RIGHT CORONARY ARTERY INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 24 MODULE 02 COMPANION GUIDE PATH 310 This content was retrieved from Seciton 01 Slide 21 of 58 of the online learning module Recall, Mr. Jones’ right coronary artery was also extensively examined. A particular histological cross section shows a substantial plaque. Learn how to interpret the diseased cross section; compare these findings to what can be seen in the healthy sample. Plaque The vessel is almost entirely occluded by the plaque, which is composed of fibronecrotic tissue. It does not stain pink like the muscular wall, which is still present but very thin. Lumen Normally, the lumen is very large in diameter, whereas in the diseased cross section from Mr. Jones, it is abnormally small. This further reduced the amount of blood available to Mr. Jones’ heart. Reference: Images courtesy of Dr. Marosh Manduch. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 25 MODULE 02 COMPANION GUIDE PATH 310 MR. JONES’ CASE: OCCLUSIVE THROMBOSIS CAUSES ACUTE MYOCARDIAL INFRACTION This content was retrieved from Section 01 Slide 22 of 58 of the online learning module The observation of a significant coronary plaque caused by an atheroma associated with plaque rupture, and subsequent superimposed thrombus formation, is the significant event that restricted blood flow, and oxygen delivery, to Mr. Jones’ heart. It is very likely that this caused further strain on Mr. Jones’ heart, leading to a first, acute myocardial infarction (MI or heart attack) which sent him to the hospital and was his initial diagnosis. Reference: NIH Image Gallery. (2017). Heart With Muscle Damage and a Blocked Artery. Flickr. Retrieved July 14, 2020, from https://www.flickr.com/photos/nihgov/33328945325 AUTOPSY REPORT: HISTOLOGY OF HEART MUSCLE This content was retrieved from Section 01 Slide 23 of 58 of the online learning module Under a microscope, the abnormalities of a diseased cardiac muscle can be seen on Mr. Jones’ samples. Typically, healthy cardiac muscle is striated with nuclei and intercalated discs present. In Mr. Jones’ case, the cardiomyocytes appear to be dying, as distinguished by coloured spots throughout the muscle. These spots are created as a result of inflammatory cells, like neutrophils, which are recruited to contain the necrotic tissue. Compare Mr. Jones’ diseased cardiac muscle to healthy cardiac muscle. MR. JONES’ SAMPLE HEALTHY SAMPLE Reference: Images courtesy of Dr. Marosh Manduch. MR. JONES’ CAUSE OF DEATH This content was retrieved form Section 01 Slide 24 of 58 of the online learning module As the M I worsened over the next few days in hospital, the muscle became necrotic and quite soft. The heart continued to pump blood; however, the soft diseased muscle tissue eventually ruptured, leading to blood exiting from inside the heart into the pericardial sac. This lead to a condition called cardiac tamponade*. Even though blood was removed from the area by the doctors, the damage done was irreversible and Mr. Jones never recovered. To review Mr. Jones’ autopsy photos, switch between a transverse and external view of Mr. Jones’ heart. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 26 MODULE 02 COMPANION GUIDE PATH 310 TRANSVERSE SECTION OF THE HEART EXTERNAL VIEW Definition*: Cardiac tamponade: Accumulation of fluid in the pericardial sac, which compromises the heart muscle and blood flow. This is considered a medical emergency. Reference: Images courtesy of Dr. Marosh Manduch. QUESTION – LOCATION OF PLAQUES AND OCCLUSIONS This content was retrieved from Section 01 Slide 25 of 58 of the online learning module Based on what y ou have learned about atherosclerosis, answer the question. List potential reasons why during the autopsy the pathologist found plaques and occlusions INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 27 MODULE 02 COMPANION GUIDE PATH 310 where they did. Feedback: Navigate to the next page to learn about the factors that influence where plaques and occlusions occur in blood vessels. View the autopsy report of the plaque locations. CULPRITS FOR ENDOTHELIAL DYSFUNCTION: HEMODYNAMIC FORCES This content was retrieved from Section 01 Slide 26 of 58 of the online learning module Endothelial dysfunction can be induced by several injurious stimuli. Hemodynamic forces are one of the key factors that are strongly correlated with endothelial dysfunction. Hemodynamic forces refer to the mechanical forces exerted due to the flow of blood. As blood flows through a vessel, it exerts two predominant forces on its walls: pressure (ρ) and shear stress (τ). See where each type of mechanical force affects the blood vessel. PRESSURE Pressure acts perpendicular to the vessel wall and affects the vascular smooth muscle (VSM) cells. SHEAR STRESS Shear stress acts parallel to the vessel wall, exerted longitudinally in the direction of blood flow. This type of mechanical force affects endothelial cell function. Reference: Hahn, C., & Schwartz, M. A. (2009). Mechanotransduction in vascular physiology and atherogenesis. Nature Reviews Molecular Cell Biology, 10(1), 53-62. Retrieved July 22, 2020, from: https://proxy.queensu.ca/login?url=http://dx.doi.org/10.1038/nrm2596 TYPES OF BLOOD FLOW This content was retrieved from Section 01 Slide 27 of 58 of the online learning module Levels of shear stress vary throughout the vasculature and can be influenced by the type of blood flow. Compare the two types of blood flow, laminar and turbulent blood flow. Note the illustrated changes in the direction and magnitude of the flow. LAMINAR BLOOD FLOW Laminar flow is the normal condition of blood flow in the circulatory system. It is characterized by blood flow parallel to the blood vessel wall and usually occurs in straight regions of arteries. This can be compared to water flowing through an open ended garden hose with no resistance. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 28 MODULE 02 COMPANION GUIDE PATH 310 TURBULENT BLOOD FLOW Laminar flow can be disrupted and become turbulent, in curved arterial regions, or where a blood vessel branches. In turbulent blood flow, conditions become disturbed and have low or oscillatory shear stress. This can be compared to putting your finger over the end of the garden hose that is running. You may also have noticed in a stream with rocks and curves that small swirls are created as the water diverts around them. References: Cunningham, K. S., & Gotlieb, A. I. (2005). The role of shear stress in the pathogenesis of atherosclerosis. Laboratory Investigation, 85(1), 9-23. Retrieved July 22, 2020, from: https://proxy.queensu.ca/login?url=https://doi.org/10.1038/labinvest.3700215 Steeley, R., Stephens, T., Tate, P. (1 January, 2013). Anatomy and Physiology 6th edition. McGraw-Hill. Pp 741. Retrieved June 23, 2020, from https://physiology.nuph.edu.ua/wp-content/uploads/2018/01/21- Cardiovascular-System-Peripheral-Circulation-and-Regulati1.pdf TURBULENT BLOOD FLOW AND ATHEROSCLEROSIS This content was retrieved from Section 01 Slide 28 of 58 of the online learning module It is in these areas of turbulent flow where the blood may swirl around and cause some dysfunction in the endothelial cells themselves or contribute to accumulation of fats that lead to plaque formation, thereby constricting the vessel. This influences the magnitude of the shear stress in the region, which can create a vicious cycle. Learn from Dr. Nicol how shear stress fluctuates between normal laminar flow and turbulent flow caused by atherosclerosis. (01:16) View the audio transcript. Start of Audio Transcript: In this graph the main take away is the difference in shear stress under laminar flow and turbulent flow. In a normal artery there's high shear stress because blood is being pumped out of the heart. Comparatively a normal vein has normal laminar flow. However, in a thrombotic or atherosclerotic region on the other hand, there's a significant decrease in shear stress in the veins, even going to the negative direction. But there's even more significant increase in the stress in your arteries. The drop in the venous stress may be related to the fact that blood is not flowing through the arteries as fast, so it's not getting to the veins. When considering the artery, it's much like a scenario where you have a hose and you place your finger over the opening and the water exists at a high pressure. The blood that gets through this constricted vessel region is shooting through at high pressure and that can cause some micro-tears and endothelial damage in the vessel wall as it goes through. Especially around curves and branch points beyond. But in addition to this, the blood that remains before the small opening, becomes turbulent and also very disruptive to the endothelial cells. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 29 MODULE 02 COMPANION GUIDE PATH 310 End of Audio Transcript. Reference: Adapted from Malek, A. M., Alper, S. L., & Izumo, S. (1999). Hemodynamic Shear Stress and Its Role in Atherosclerosis. JAMA, 282(21), 2035-2042. Retrieved June 23, 2020, from: https://proxy.queensu.ca/login?url=https://doi.org/10.1001/jama.282.21.2035 QUESTION – LOCATION OF ATHEROSCLEROTIC LESIONS This content was retrieved from Section 01 Slide 29 of 58 of the online learning module Hemodynamic forces are responsible for dictating which vascular sites are susceptible or resistant to developing atherosclerosis. Using what you have learned about blood flow, shear stress, and atherosclerosis, answer the question. Question: Which regions in the vasculature are prone to the development of an atherosclerotic lesion? Explain the role of hemodynamic forces in predisposing these regions to endothelial dysfunction and subsequently atherosclerosis. Feedback: Compare your response to Dr. Nicol’s response. FEEDBACK: LOCALIZATION OF ATHEROSCLEROSIS LESIONS This content was retrieved from Section 01 Slide 30 of 58 of the online learning module Question: Which regions in the vasculature are prone to the development of an atherosclerotic lesion? Explain the role of hemodynamic forces in predisposing these regions to endothelial dysfunction and subsequently atherosclerosis. Continue to compare your response to Dr. Nicol’s response. Your Response Dr. Nicol’s Response Atherosclerotic lesions develop predominantly in arterial curves, bifurcations, and branch sites. This includes the aorta, carotid arteries, coronary arteries, renal arteries, and arteries of the lower extremities. You can now appreciate how these regions would force changes in blood flow and shear stress, but there are also molecular underpinnings to these changes, which you will explore next. Reference: LadyofHats. (2010). Circulatory System no tags. Wikimedia Commons. Retrieved June 2020, from https://commons.wikimedia.org/wiki/File:Circulatory_System_no_tags.svg INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 30 MODULE 02 COMPANION GUIDE PATH 310 SHEAR STRESS, ENDOTHELIAL DYSFUNCTION, AND ATHEROSCLEROSIS This content was retrieved from Section 01 Slide 31 of 58 of the online learning module Research has demonstrated a correlation between shear stress, endothelial dysfunction, and atherosclerosis. It is suggested that laminar blood flow induces endothelial cells to express genes that protect against atherosclerosis. These genes are implicated in normal endothelial function. Regions with turbulent blood flow can impair endothelial phenotype and function, and are prone to atherosclerosis. This is because disturbed blood flow exerts low/oscillatory shear stress on the vessel wall allowing deposits of fats to form or inducing other endothelial cell dysfunction. References: Cunningham, K. S., & Gotlieb, A. I. (2005). The role of shear stress in the pathogenesis of atherosclerosis. Laboratory Investigation, 85(1), 9-23. Retrieved June 23, 2020 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1038/labinvest.3700215 Mehta, V., & Tzima, E. (2016). A turbulent path to plaque formation. Nature, 540(7634), 531-532. Retrieved June 23, 2020 from: https://proxy.queensu.ca/login?url=https://doi.org/10.1038/nature20489 EFFECT OF SHEAR STRESS ON ENDOTHELIAL CELL PHENOTYPE This content was retrieved from Section 01 Slide 32 of 58 of the online learning module Under experimental conditions, when normal endothelial cells are exposed to low shear stress, changes in the endothelial cell morphology are observed. Compare the effects on normal endothelial cell phenotypes when exposed to physiological compared to low shear stress. PHYSIOLOGICAL SHEAR STRESS Endothelial cells exposed to physiological arterial shear stress (> 15 dynes/cm2); cells are elongated and aligned to the direction of blood flow to increase the aerodynamics of their shape and minimize interference with vessel components. LOW SHEAR STRESS Endothelial cells exposed to low arterial shear stress (0-1 dynes/cm2); cells have a cobblestone appearance. Genetic changes also occur when these cells are impacted by changes in shear stress that will be explored on the next slide." Reference: Topper, J. N., & Gimbrone Jr, M. A. (1999). Blood flow and vascular gene expression: fluid shear stress as a modulator of endothelial phenotype. Molecular Medicine Today, 5(1), 40-46. Retrieved June 23, 2020, from: https://proxy.queensu.ca/login?url=https://doi.org/10.1016/S1357-4310(98)01372-0 INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 31 MODULE 02 COMPANION GUIDE PATH 310 SHEAR STRESS AND KEY REGULATOR GENES OF INFLAMMATION This content was retrieved from Section 01 Slide 33 of 58 of the online learning module Endothelial cell inflammatory phenotypes, in response to their shear stress environments, are controlled by a few key regulator genes. Learn about the changes induced by laminar and turbulent shear stress. LAMINAR SHEAR STRESS Under laminar shear stress, endothelial cells express genes like KLF2 or Nrf2. These genes act in a protective manner and help inhibit the expression of NFᴋB , a pro-inflammatory transcription factor. TURBULENT SHEAR STRESS Under turbulent shear stress, the expression of protective genes is lost, therefore, NFᴋB is upregulated to create a pro-inflammatory environment in blood vessels. This allows for the recruitment of monocytes and macrophages to initiate plaque formation and enables smooth muscle cells to proliferate. SHEAR STRESS AND MASTER REGULATOR GENES This content was retrieved from Section 01 Slide 34 of 58 of the online learning module The presented diagram shows the complex interaction of many genes. It is not important to focus on the specific molecular pathways, but instead understand the impact that the master regulators, Nrf2 and KLF2, have on the endothelial environment under laminar shear stress conditions. As you just learned, laminar shear stress will upregulate KLF2, which turns on Nrf2. Together, upregulation of these genes results in the blockade of oxidative stress and inflammatory pathways (including NFκB), while upregulating factors that help block thrombosis. Upregulated KLF2 and Nrf2 genes also increase the communication in vascular tone, which can help set the stage for improving conditions to minimize the development of atherosclerotic plaques. These two genes play an important role in minimizing the oxidation/oxidative stress of the lipids that get out from the lumen, under the tunica intima into the tunica media. Reference: Image courtesy of Dr. Christopher Nicol. QUESTION – THE EFFECT OF SHEAR STRESS ON ENDOTHELIAL PHENOTYPE This content was retrieved from Section 01 Slide 35 of 58 of the online learning module Consolidate what you know about hemostasis and atherosclerosis by choosing whether a certain component is increased/upregulated (↑) or decreased/downregulated (↓) in each region and phenotype. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 32 MODULE 02 COMPANION GUIDE PATH 310 Options: ↑, ↓ Activated Phenotype: Turbulent Shear Stress ↑ or ↓ ? Coagulation PGL2, NO, tPA Platelet aggregation Endothelium Proliferation Apoptosis Alignment Inflammatory State SMC proliferation Leukocyte adhesion Quiescent Phenotype: Laminar Shear Stress ↑ or ↓ ? Coagulation PGL2, NO, tPA Platelet aggregation Endothelium Proliferation Apoptosis Alignment Inflammatory State SMC proliferation Leukocyte adhesion Feedback: Activated Phenotype: Turbulent Shear Stress ↑ or ↓ ? Coagulation PGL2, NO, tPA ↑ Platelet aggregation ↓ Endothelium Proliferation ↓ Apoptosis ↓ Alignment ↑ Inflammatory State SMC proliferation ↓ INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 33 MODULE 02 COMPANION GUIDE PATH 310 Leukocyte adhesion ↓ Quiescent Phenotype: Laminar Shear Stress ↑ or ↓ ? Coagulation PGL2, NO, tPA ↓ Platelet aggregation ↑ Endothelium Proliferation ↑ Apoptosis ↑ Alignment ↓ Inflammatory State SMC proliferation ↑ Leukocyte adhesion ↑ Proceed to the next slide for further feedback on this consolidation activity. FEEDBACK: THE EFFECT OF SHEAR STRESS ON ENDOTHELIAL PHENOTYPES This content was retrieved from Section 01 Slide 36 of 58 of the online learning module The molecular knowledge of how endothelial cells are affected by shear stress helps explain the development of atherosclerotic plaques. The presented table summarizes these relationships. Review different representations of these processes. COMPARISON TABLE Quiescent Phenotype: Activated Phenotype: Laminar Shear Stress Turbulent Shear Stress Coagulation ↑PGL2, NO, tPA ↓PGL2, NO, tPA ↓Platelet aggregation ↑Platelet aggregation Endothelium ↓Proliferation ↑Proliferation ↓Apoptosis ↑Apoptosis ↑Alignment ↓Alignment Inflammatory State Anti-inflammatory Anti-inflammatory ↓SMC proliferation ↑SMC proliferation ↓Leukocyte adhesion ↑Leukocyte adhesion LAMINAR FLOW DIAGRAM INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 34 MODULE 02 COMPANION GUIDE PATH 310 TURBULENT FLOW DIAGRAM Reference: Diagram: Bergan, J. J., Schmid-Schönbein, G. W., Coleridge Smith, P. D., Nicolaides, A. N., Boisseau, M. R., and Eklof, B. (2006). Chronic Venous Disease. New England Journal of Medicine, 355(5): 494. Retrieved June 23, 2020, from: https://www-nejm-org.proxy.queensu.ca/doi/full/10.1056/NEJMra055289 CASE PRESENTATION: MR JONES’ SON This content was retrieved from Section 01 Slide 37 of 58 of the online learning module For the remainder of this section, you will focus on Mr. Jones’ son, who arrived at the emergency department a few months after his dad passed away, complaining of chest pains. View his patient history and test results. Patient Medical History 35-year-old male of French-Canadian ancestry experiencing chest pain when active Father recently passed away (at age 59) from acute MI due to atherosclerosis History: smoker of 10 cigarettes per day for last 20 years Xanthomas* were found on his eyelids and knees upon performing a physical exam Test Results INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 35 MODULE 02 COMPANION GUIDE PATH 310 Blood pressure: 136 mmHg/86 mmHg (high) BMI*: 30 kg/m2 (obese) Blood test results: o Triglycerides (TG): 160 mg/dl o High Density Lipoproteins (HDL): 38 mg/dl o Low Density Lipoproteins (LDL): 207 mg/dl o Total Cholesterol: 245 mg/dl Definitions*: Xanthomas: Cholesterol deposits found under the skin. They can be found on joints (elbows, knees), eyelids, and ankle tendons. BMI: Body mass index; a measure of body fat based on height and weight that applies to adult men and women. QUESTION – MR. JONES’ RISK FACTORS This content was retrieved from Section 01 Slide 38 of 58 of the online learning module The underlying etiology of atherosclerosis is unknown, however, as you can recall, certain factors may increase the risk of developing atherosclerosis. These factors can be distinguished as modifiable* and non-modifiable*. Question: Based on what you know from Mr. Jones’ case, determine if his son’s risk factors are modifiable or non-modifiable. RISK FACTORS Modifiable Non-Modifiable Unknown Hyperlipidemia Family History Gender Hypertension Cigarette smoking Increasing age Feedback: RISK FACTORS Modifiable Non-Modifiable Unknown Hyperlipidemia Unknown Family History Non-Modifiable Gender Non-Modifiable Hypertension Modifiable Cigarette smoking Modifiable Increasing age Non-Modifiable Listen to Dr. Nicol’s feedback. (00:44) View the audio transcript. Start of Audio Transcript: INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 36 MODULE 02 COMPANION GUIDE PATH 310 Based on the patient history and Mr. Jones' autopsy results, Mr. Jones' son is also suspected of having atherosclerosis. His family and medical history certainly predispose him to developing this disease. And you may also appreciate that Mr. Jones' son has a few modifiable risk factors related to his lifestyle. Such as cigarette smoking and hypertension. His hyperlipidemia may also be modifiable but we won't know for sure if this is true until more information is obtained. Using your knowledge from Mr. Jones' case you will assist the healthcare team in treating Mr. Jones' son through his modifiable risk factors. End of Audio Transcript. Definitions*: Modifiable: Health or medical measures can be taken to influence the outcome of a disease. Non-modifiable: No measures can be taken to change its influence on the disease. CULPRITS FOR ENDOTHELIAL DYSFUNCTION: HYPERLIPIDEMIA This content was retrieved from Section 01 Slide 39 of 58 of the online learning module In addition to changes in shear stress conditions, endothelial dysfunction can also be induced by hyperlipidemia, which refers to abnormally high levels of lipids in the blood. Given the medical history of his father and his high B M I observed on admission to the emergency department, you decide to investigate that the possibility that Mr. Jones' son may also have hyperlipidemia, which could predispose him to atherosclerosis. This may or may not be an modifiable risk factor. Recall from previous courses that lipids are a group of hydrophobic organic molecules that include triglycerides* and cholesterol*. Lipids are usually hydrophobic and hence remain insoluble in water, blood plasma, and other extracellular fluids. In order to transport these lipids in the blood plasma, specialized proteins such as lipoproteins are used. Review the types of lipoproteins. REVIEW OF LIPOPROTEINS - Refer to Pages 38-39 Definitions*: INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 37 MODULE 02 COMPANION GUIDE PATH 310 Triglycerides: An ester derived from glycerol and three fatty acids. The principle component of body fat in humans. Cholesterol: A sterol, a type of lipid, involved in cell growth, cell division, membrane repair, steroid hormone production. Reference: Servier Medical Art. (n.d.). Atheroma. Retrieved May 11 2020, from https://smart.servier.com/smart_image/atherosclerosis-23/ REVIEW OF LIPOPROTEINS Subpage of Section 01 Slide 39 of 58 – Review of Lipoproteins 1/1 Lipoproteins organize triglycerides and cholesterol into a plasma-soluble complex and in doing so provide a lipid delivery system. Learn about the different protein and lipid compositions. CM Chylomicrons (CM) are the least dense lipoproteins assembled in the intestinal mucosal cells. They are primarily composed of triglycerides and a small amount of protein. Chylomicrons carry dietary triacylglycerol from the intestinal tract to the tissues. VLDL Very low density lipoproteins (VLDL) consist mainly of triglycerides, some cholesterol molecules, and very few protein molecules. Similar to the chylomicrons, VLDL delivers triglycerides to cells in the body for cellular processes. IDL VLDL is converted into intermediate density lipoprotein (IDL). After the triglycerides on VLDL have been broken down in cells, the lipid to protein ratio changes and the lipoprotein becomes denser. LDL Low density lipoprotein (LDL) is synthesized in the blood from VLDL/IDL and is very rich in cholesterol. L DL is the main transporter of cholesterol to peripheral tissues, a process known as cholesterol transport. HDL High density lipoprotein (HDL) consists of less cholesterol and more protein, making these lipoproteins the most dense. HDL is a key mediator of reverse cholesterol transport which involves carrying cholesterol from cells back to the liver. Reference: INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 38 MODULE 02 COMPANION GUIDE PATH 310 Lumen Learning. (n.d.). Lipoproteins. Nutrition Flexbook. Retrieved 30 April 2020, from https://courses.lumenlearning.com/suny-nutrition/chapter/4-71-lipoproteins/ REVERSE CHOLESTEROL TRANSPORT This content was retrieved from Section 01 Slide 40 of 58 of the online learning module Reverse cholesterol transport is involved in the modulation of the total lipid profile. This is a mechanism by which the body removes excess cholesterol from peripheral tissues and delivers it to be broken down in the liver and excreted. The key mediator in this process is HDL. Listen to Dr. Nicol describe the process of lipid transport and the important role of reverse cholesterol transport. (02:41) View the audio transcript. Start of Audio Transcript: Normally the fats in your diet are absorbed and turned into triglycerides and cholesterol in the liver. These then associate with lipoproteins which transport to your fat cells, starting with the formation of very low density lipoproteins in the liver, a cycling process converts them to LDLs which may be utilized by the normal body needs for lipids such as maintaining cell membranes, stored in fat cells, or broken down for excretion via the bile. LDL receptors located on cell surfaces bind circulating LDL and bring it inside the cell, helping to maintain normal blood cholesterol levels. In extrahepatic cells or scavenger cells such as macrophages, LDL receptors also soak up LDL to break it down and may either store it or prepare it for excretion. Normally the body will work to eliminate excess levels of cholesterol and does so with the help of high density lipoproteins or HDL. It's worth noting at this point that HDL is commonly thought of as, quote unquote, a good fat, while VL DL and LDL are considered the quote unquote, bad fats. Just remember, the body needs fats to function normally too. Therefore, it may be better to think about these in terms of having a normal balance and/or a good reserve capacity to break down and eliminate excess fats as being good and an imbalance that favours excess storage or circulation of fats being bad. Normally you have fats that you eat and fats that you excrete through the bile. However, some fats associate with chylomicrons and get broken down by lipoprotein lipase enzymes that form HDL, the good fat. That helps cycle the excess bad cholesterol back for elimination. When L DL is broken down, it releases cholesterol which associates with HDL and travels back to the liver so it can be used again or excreted in the bile as we talked about above. This process is known as reverse cholesterol transport. This is where the levels of fats in the body become important. When looking at indicators maintaining high levels of HDL are ideal to reduce any potentially high levels of VLDL or LDL to ensure an appropriate recycling through the reverse cholesterol transport system. End of Audio Transcript. Reference: Image courtesy of Dr. Christopher Nicol. THE IMPORTANCE OF HDL IN REVERSE CHOLESTEROL TRANSPORT This content was retrieved from Section 01 Slide 41 of 58 of the online learning module INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 39 MODULE 02 COMPANION GUIDE PATH 310 HDL facilitates reverse cholesterol transport, an important process that can help reduce the presence of atherosclerotic plaques. Watch the video to solidify your understanding of the principles of this process. (03:23) Note: Knowledge of the names/details of the receptors and pathways are not expected, however your focus should be on the principles of this process. Page Link: https://www.youtube.com/embed/q0YiPqmsXRg Reference: Tagouz. (2013, October 18). HDL & Reverse Cholesterol Transport [HD] [Video]. YouTube. Retrieved 8 July, 2020 from https://www.youtube.com/watch?v=q0YiPqmsXRg ROLE OF FATS IN ATHEROSCLEROSIS This content was retrieved from Section 01 Slide 42 of 58 of the online learning module Normally, endothelial cells do not adhere to leukocytes. However, recall from the pathophysiology of atherosclerosis that dysfunctional endothelial cells also are able to mediate the adhesion and migration of leukocytes (e.g. monocytes and T-lymphocytes), a process which is mediated by a receptor called VCAM-1. When an atherogenic diet high in saturated fats and cholesterol is introduced, scientists have observed an increase in VCAM-1 expression in endothelial cells. They have also observed an increase in leukocyte adhesion to the endothelium. This suggests that hyperlipidemia promotes atherosclerosis through leukocyte adhesion. A simple way to start to narrow down the possibility of Mr. Jones’ son having hyperlipidemia is to take a blood sample before a meal, which you dutifully conduct. ROLE OF FATS IN ATHEROSCLEROSIS: MR. JONES’ SON’S BLOOD This content was retrieved from Section 01 Slide 43 of 58 of the online learning module Review the presented vials of centrifuged blood; a healthy patient sample (A) is provided as a reference against a sample from Mr. Jones’ son (B). What do you observe? Once ready, review some reflections from Dr. Nicol. BLOOD SAMPLE ANALYSIS As you may appreciate, the bottom portion of each vial contains the erythrocyte component of the sample. In the case of the healthy patient, there is a semi-transparent serum present above the blood layer. INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 40 MODULE 02 COMPANION GUIDE PATH 310 In Mr. Jones’ son’s case, the serum is almost completely taken up by a layer of yellow-white, opaque lipid. For approximately the same amount of blood that was spun down, there is an equivalent amount of lipid flowing in his bloodstream. Imagine how difficult it must be for the blood to flow through the circulation with such a viscous substance. With this visual indication of such a significant presence of lipids in his circulation, it certainly suggests to you that he likely has an associated higher risk of developing atherosclerosis. Reference: Hyperlipemia and Hepatic Lipidosis in Large Animals - Digestive System. (n.d.). Retrieved 16 June 2020, from https://www.merckvetmanual.com/digestive-system/hepatic-disease-in-large- animals/hyperlipemia-and-hepatic-lipidosis-in-large-animals PLASMA LIPID LEVELS AND ASSOCIATED HEALTH RISKS This content was retrieved from Section 01 Slide 44 of 58 of the online learning module You decide to review Mr. Jones’ son’s blood test results again, specifically for the plasma lipid levels. These levels can provide additional clues as to the cause of the high presence of lipids in his blood and potential effect on his health. Mr. Jones’ Son Triglycerides (TG): 160 mg/dL High Density Lipoproteins (HDL): 38 mg/dL Low Density Lipoproteins (LDL): 207 mg/dL Total Cholesterol: 245 mg/dL Go through the different lipoprotein reference tables to learn their appropriate and abnormal levels and compare them to the patient’s blood test results. NORMAL PLASMA LIPID LEVELS Triglycerides Total H D L (mg/dL) TC/HDL-C (mg/dL) Cholesterol (m g/dL) Adult Female 80 190 55 3.5 Adult Male 120 200 43 4.7 Neonate 35 70 35 2.0 Definition: TC/HDL-C: This is a ratio of Total Cholesterol to HDL. This number is obtained by dividing total cholesterol levels by HDL levels. A higher ratio means higher risk for disease, and a lower ratio means a lower risk for disease. It is optimal for a ratio to be below 5. TRIGLYCERIDE LEVELS INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 41 MODULE 02 COMPANION GUIDE PATH 310 Triglyceride Level Category Less than 150 m g/dL Normal 150-199 m g/d L Borderline High 200-499 m g/d L High 500 m g/d L and above Very High HDL-CHOLESTEROL LEVELS HDL Cholesterol Level Category Less than 40 mg/dL A major risk factor for heart disease. 40-50 mg/dL The higher your HDL level, the better. 60 mg/dL and above Considered protective against heart disease. LDL-CHOLESTEROL LEVELS LDL Cholesterol Level Category Less than 100 mg/dL Optimal 100-129 mg/dL Near or above optimal 130-159 mg/dL Borderline high 160-189 mg/dL High 190 mg/dL and above Very high For interest, review a note about the terms H D L-C and L D L-C. Of minor technical interest, HDL-Cholesterol levels and LDL-Cholesterol levels represent the measure of cholesterol associated with each type of particle (e.g. tells how much HDL or LDL is present but is really an indirect measure) and often used interchangeably with HDL/LDL even though they are not the same. In this course, if referring to results of a blood test, HDL-C or LDL-C is likely best to use, but other places where we mean the particles themselves, we can just use the term HDL or LDL. QUESTION – TC/HDL RATIO This content was retrieved from Section 01 Slide 45 of 58 of the online learning module Based on what you just learned about total cholesterol and HDL ratios, answer the question. Question: If Mr. Jones’ son has an HDL level of 38 mg/dL, a total cholesterol of 245 mg/dL, and a triglyceride level of 160 mg/dL, what is the TC/HDL ratio and what is his risk of cardiovascular disease? a) Ratio is 4.2; risk is very high. b) Ratio is 6.4; risk is low. c) Ratio is 4.2; risk is very low. d) Ratio is 6.4; risk is high. Dr. Nicol’s Feedback: The correct response is d). INTRODUCTION TO PATHOLOGY AND MOLECULAR MEDICINE | PATH 310 MODULE 02 PAGE 42 MODULE 02 COMPANION GUIDE PATH 310 Mr. Jones’ son’s TC/HDL ratio is 6.4. You calculate this number by dividing 245 mg/dL by 38 mg/dL. Since the ratio is above 5, the optimal range, you can assume his ratio of developing cardiovascular disease is high. Mr. Jones’ son’s plasma lipid levels are all outside the optimal ranges of: TG