Atherosclerosis Session 20 - PDF

Lesson: Atherosclerosis Session: 20 Instructor: Dr. Nowgh As you know, the arterial wall comprises three layers: intima (consisting of endothelial cells and basement membrane), media (consisting of smooth muscles and external elastic membrane), and adventitia. All arteries share this wall structu...

Lesson: Atherosclerosis Session: 20 Instructor: Dr. Nowgh As you know, the arterial wall comprises three layers: intima (consisting of endothelial cells and basement membrane), media (consisting of smooth muscles and external elastic membrane), and adventitia. All arteries share this wall structure. Arterioles, which are resistance vessels, have a thicker media layer and respond significantly to hormonal and humoral factors. The intima layer is the site of atherosclerosis manifestation. Arteriosclerosis is a general term meaning hardening and loss of elasticity of the arterial walls, and it has three types: 1. Atherosclerosis The most common and significant type, initiated by the entry of LDL molecules into the subintima of the arterial walls. 2. Monckberg Medial Calcific Sclerosis (Medial Sclerosis): Typically seen in individuals over 50 years or specific populations, characterized by calcification and stiffening of the arterial walls, visible via radiography, affecting the media layer. 3. Arteriolosclerosis: Hardening and thickening of small arteries (arterioles), less than 100 microns. For instance, arterioles in the afferent and efferent glomerular arterioles in the kidney, where arteriolosclerosis can initiate kidney disease. Atherosclerosis Development: A cross-section of a normal artery includes three layers: intima, media, and adventitia. Arterial walls have a thicker smooth muscle (media) layer compared to venous walls. The stages include: 1. Foam Cell Formation: Atherosclerosis usually begins at birth in arteries and progresses notably in coronary arteries from age 51, making it a physiological phenomenon. The primary role in atherosclerosis is played by LDL cholesterol molecules. Increased permeability of LDL molecules in the bloodstream to the subintima region leads to their accumulation. Excess LDL molecules are  phagocytosed by macrophages, forming foam cells. These foam cells eventually break down, releasing LDL back into the bloodstream for metabolism. Any factor accelerating LDL penetration into the subintima sets the stage for atherogenesis, including: *Structural Defects and LDL Oxidation: Any structural defect, including LDL oxidation, increases their affinity to endothelial cells, making it easier for LDL to pass through the endothelium. This explains why antioxidants can help prevent atherosclerosis. Other abnormalities, like LDL glycosylation, also play a role. Endothelial Cell Factors: Factors that affect endothelial cells and cause endothelial damage are critical. Endothelial cells must lose their function to allow LDL to pass through. Fatty Streak Formation: When a large amount of LDL enters the subintima, more leukocytes and monocytes are attracted to the area to engulf the LDL. Monocytes engulfing more LDL than they can digest accumulate LDL inside them, becoming foam cells. This process forms fatty streaks, which are early atherosclerotic lesions. Increased LDL molecules in the subintima and their phagocytosis create foam cells, whose destruction releases mediators with various properties like attracting more inflammatory cells and inducing smooth muscle cells from the media layer to migrate into the subintima, forming fibrous tissue. Thus, these lesions consist of foam cells, monocytes, macrophages, and fibrous and smooth muscle cells. The first visible lesion in atherosclerosis is the fatty streak, which is more advanced than foam cells, as it includes fibroblasts. lesion Progression: As atherosclerotic lesions grow, they narrow the vessel lumen, disrupting blood flow. Normal blood flow is laminar, but narrowing causes turbulent flow, leading to further endothelial damage. Intermediate Lesion: Next, the intermediate lesion stage occurs, characterized by a larger lesion. Atheroma At this stage, the lesion's volume increases, becoming an atherosclerotic plaque (Atherogenesis plaque). Atherosclerosis involves cell accumulation, primarily fibroblasts, inflammatory cells, monocytes, macrophages, and lymphocytes (especially T cells). Pathways of Atheroma: One consequence of atheroma enlargement is vessel lumen narrowing, causing ischemia, potentially leading to angina and myocardial infarction (MI). The high fibroblast content and fibrin secretion can form a fibrous plaque, a very firm lesion. This plaque can further grow, narrowing the vessel lumen. Acute Complications Sudden acute complications can occur, especially under stress, due to catecholamine release and increased blood flow through the plaque. This may lead to endothelial cell detachment from the plaque surface... Plaque Rupture and Complications When a plaque ruptures, its inflammatory contents are exposed to the bloodstream, rapidly attracting platelets to the site, causing platelet adhesion and aggregation. This process leads to clot formation, vessel blockage, and potentially sudden death. Plaque rupture is a severe complication. Another complication is sudden plaque hemorrhage. When the plaque is extensive, the sudden opening of a vasa vasorum (small blood vessel) within the plaque due to increased plaque volume can block the vessel lumen, causing acute symptoms and myocardial infarction (MI). Atherogenesis and Risk Factors: As previously mentioned, the progression of atherogenesis in medium and large arteries starts from birth and intensifies based on risk factors. Endothelial cells are highly active and functionally diverse. Endothelial cells produce humoral factors: vasodilators that relax the vascular smooth muscle cells and vasoconstrictors that tighten vessels. The balance of these factors is crucial. If endothelial function is impaired, it may increase vasoconstrictor action, causing vasospasm and narrowing, leading to pathophysiological conditions. Conversely, an increase in vasodilators can cause blood vessel dilation, referred to as coronary artery ectasia, where blood pools and flows turbulently, leading to sym ptomatic patients. The regular movement and flow of blood through vessels depend on the smooth muscle cells' tone, controlled by endothelial cells and the balanced production of vasodilators and vasoconstrictors. Known vasodilators include nitrates, and vasoconstrictors include thromboxane A2. In normal blood flow, which is laminar, oxygen is delivered to tissues efficiently. Atherosclerotic plaque formation narrows the vessel lumen, disrupting normal laminar flow and creating turbulent flow. Turbulent flow further damages endothelial cells. Stages of Atherogenesis: The progression of atherogenesis starts from initial endothelial dysfunction (due to LDL infiltration and macrophage and monocyte entry), advancing to fatty streaks, intermediate lesions, and atheromas. This intricate process in vascular atherogenesis and the transformation from fibro-fatty plaque to advanced plaque can eventually lead to lumen narrowing or other severe complications. In the upper form, the stages of vascular atherogenesis as well as the process of conversion of fibrofatty plaque to advanced plaque are seen. Also, as it has been shown, this pulp can progress so much that it causes a **Rupture and Thrombus Formation:**narrowing of the lumen, or 4 rapture plaques or clot formation is seen, or a hemorrhage enters the pulley, where the volume of the pulp causes a sudden closure of the vessel wall Plaque rupture exposes inflammatory contents to the bloodstream, attracting platelets, causing adhesion and aggregation, leading to clot formation, vessel blockage, and potentially sudden death. Another complication is sudden plaque hemorrhage, which can cause sudden vessel lumen closure due to vasa vasorum rupture. **Aspirin in Plaque Management:** Aspirin, an important antiplatelet drug, inhibits cyclooxygenase (COX), reducing thromboxane A2 and platelet aggregation. However, it also reduces prostacyclin (PGI2), an important vasodilator, potentially increasing vasoconstrictors and causing endothelial damage. Thus, aspirin has a dual effect. Aspirin changes As an analgesic and anti-inflammatory, the dose is 100 mg/kg, about 4-6 grams for an adult. For coronary disease, it's 1 mg/kg, typically 80 mg for patients. Aspirin is absorbed into the portal system, affecting platelet thromboxane production permanently in about 25% of circulating platelets. However, much is metabolized in the liver, not reaching systemic circulation. **Symptomatic Atherosclerotic Plaque:** - Less than 50% vessel diameter narrowing: No symptoms, even with intense activity. - 50-75% vessel diameter narrowing: No symptoms at rest, but symptomatic during activity. - Over 75% vessel diameter narrowing: Symptomatic at rest. Does this cover what you need, or do you have more to dive into? In the diagram above, the progression of atherosclerosis and how advanced plaque causes clinical disease is shown. This includes critical stenosis, aneurysm and rupture, and occlusion by thrombus. **Acute Coronary Syndrome (ACS):** A collection of clinical symptoms caused by coronary artery disease, leading to myocardial ischemia. ACS can be further divided: 1. **Unstable Angina:** No myocardial necrosis, but clinical presentation of myocardial ischemia. 2. **Myocardial Infarction (MI):** If the infarction is transmural (affecting the entire heart wall), it is usually associated with ST-segment elevation on ECG, termed ST Elevation MI. Non-transmural MI, without ST-segment elevation, but with myocardial necrosis, is termed Non-ST Segment Elevation MI (NSTEMI).  **Stable Angina:** Any stable angina was initially unstable. If an unstable angina does not change for at least a month, it is termed stable angina. **Coronary Syndromes:** Symptoms due to coronary artery disease (mostly caused by atherosclerosis) are divided into Stable Coronary Syndrome and Acute Coronary Syndrome. Stable coronary disease causes a certain level of myocardial ischemia that remains stable for over a month, unless exacerbated by an event. **Atherosclerosis Risk Factors:** Factors accelerating atherosclerosis are: - **Modifiable:** High cholesterol levels, smoking, hypertension (HTN), diabetes, physical inactivity, and obesity. Lowering cholesterol can delay or control atherosclerosis. - **Non-modifiable:** Family history (genetic predisposition), aging, male gender, and non-white race. **Atherosclerosis Risk Factors:** Divided into major (traditional) and minor (non- traditional). Major risk factors have a direct, definite link with the disease, while minor risk factors do not. Over 200 minor risk factors are recognized. *Major Risk Factors:** **Smoking:** A major risk factor, significantly worsening atherosclerosis, depending on the amount and duration of smoking and other factors. Smoking directly damages endothelial cells and increases fibrinogen levels, disrupting endothelial function and LDL molecules. If someone quits smoking, their fibrinogen levels return to normal in about two years. Smoking also induces hypoxia. **Diabetes:** Uncontrolled diabetes for ten years inevitably causes arterial atherosclerosis. Hyperglycemia in diabetes leads to endothelial dysfunction, increasing LDL adhesion to the endothelium. Glycosylation of endothelial cells allows more LDL  molecules to enter the subintima. Diabetic patients also exhibit lipid abnormalities, such as microalbuminuria, which exacerbates atherosclerosis. **High Blood Pressure (Hypertension):** Hypertension impairs endothelial cell function, promoting increased LDL infiltration into the subintima and accelerating atherosclerosis progression. **Lipid Disorders (Hyperlipidemia):** Blood lipids include triglycerides and cholesterol, present as LDL and HDL. The core of atherosclerosis lies in LDL molecules, whereas HDL protects against atherosclerosis. LDL transports lipoproteins and cholesterol from the liver to tissues, while HDL carries excess cholesterol from tissues to the liver for metabolism. **Optimal Lipid Levels:** - **LDL Cholesterol:** Optimal level is less than 100 mg/dL. For those with coronary artery disease, it should be below 70 mg/dL. - **Total Cholesterol:** Should be below 200 mg/dL. - **HDL Cholesterol:** Should be above 40 mg/dL; below this is a risk factor itself. **Mechanism:** Higher LDL levels in circulation increase the likelihood of LDL binding to endothelial cells and their oxidation, raising the risk of atherosclerosis. **Family History:** Having a family member with coronary atherosclerosis under 55 years in the paternal family or under 65 years in the maternal family indicates a genetic influence, making it a major risk factor. This usually means higher LDL affinity for endothelial cells. **Sedentary Lifestyle:** Lack of physical activity contributes significantly to atherosclerosis. **Kidney Disease:** Another contributing factor. **Minor Risk Factors:** - Chronic inflammatory diseases (as some believe atherosclerosis is inflammatory). - High homocysteine levels. - Presence of C-reactive protein (CRP). - Lipoprotein abnormalities. - Metabolic disorders. - High fibrinogen levels. - Kidney diseases. - HIV. - Electrolyte imbalances (e.g., calcium or magnesium changes). Those with higher dietary intake of these nutrients from seafood and vegetables are less prone to atherosclerosis. - Gender: Being male increases the risk and it typically presents a decade earlier in men, likely due to hormonal factors. **Myocardial Demand and Supply Balance:** - **Demand Factors:** 1. **Heart Rate:** Higher heart rates increase demand. 2. **Contractility:** Stronger heart contractions elevate demand.  3. **Systolic Wall Tension (afterload):** Increased preload and afterload raise ventricular wall tension and, subsequently, demand. - **Supply Factors:** 1. **Coronary Blood Flow:** Mainly during diastole, factors affecting it include... By keeping the balance between supply and demand in the myocardium, we can manage ischemic heart disease (IHD). Anything else you want to dive into? **A) Diastolic Phase:** Coronary arteries fill during diastole. So, the shorter the diastolic phase (e.g., tachycardia), the less coronary blood flow. **B) Vascular Resistance:** Factors affecting vascular resistance in small myocardial arteries include: - **Metabolic Control** - **Autoregulation:** Coronary arteries can adjust their diameter based on demand. - **Extravascular Compressive Forces** - **Humoral Factors:** Hormones affecting coronary artery diameter, released by endothelial cells. - **Neural Control:** The sympathetic system (catecholamines causing arteriolar constriction) and parasympathetic system. **Oxygen-Carrying Capacity:** For instance, someone with anemia has reduced oxygen-carrying capacity and might experience myocardial ischemia despite not having coronary artery disease. Carboxyhemoglobin toxicity (CO binding to hemoglobin) lowers oxygen-carrying capacity, leading to ischemia.  **Atherosclerosis Impact:** When a vessel is atherosclerotic, plaque narrows the lumen and disrupts blood flow. During increased myocardial oxygen demand, the compromised flow fails to meet oxygen needs, causing ischemia. Major factors affecting coronary blood flow include the diameter of epicardial arteries influenced by atherosclerosis and humoral factors. Patients with 50% stenosis might differ symptomatically due to humoral factors. **Myocardial Ischemia:** Characterized by chest pain, termed acute coronary syndrome (ACS). Plaques alter blood flow based on their volume, influencing symptoms. Stenosis under 50% typically doesn't cause symptoms due to vasodilation compensations. Stenosis between 50- 75% causes symptoms during activity but not at rest. Stenosis over 75% results in symptoms even at rest. **Angina** **Main Symptom:** The most significant clinical symptom of myocardial ischemia, presenting as chest pain known as angina pectoris. **Features of Angina:** - **Location:** Typically retrosternal, felt behind the sternum. It can be anywhere from the navel to the jaw, often epigastric, but most commonly retrosternal. The pain cannot be localized. - **Duration:** Typically lasts 5 to 15 minutes, but can range from 20 seconds to 20 minutes. Pain lasting over 20 minutes may indicate myocardial infarction (MI) or non- anginal pain.  - **Triggers:** Stress, excitement, walking, arguing. Typical angina is controlled within 5 minutes by nitroglycerin (TNG) or rest. - **Quality:** Anginal pain is vague, non-localizable, burning, or squeezing. Some may only feel shortness of breath. - **Associated Symptoms:** Based on the sympathetic system (sweating, anxiety, panic) and parasympathetic system (nausea, vomiting, dizziness). Inferior MI often shows parasympathetic signs, while anterior MI shows sympathetic signs. - **Radiation:** Typically radiates to other areas, especially the inner left arm and forearm. Symptoms can vary in location and accompanying signs. **Acute Coronary Syndrome (ACS):** If typical angina occurs within the past month. **Differential Diagnoses for Chest Pain:** Chest pain can have many causes, not necessarily myocardial disorders. Including: - **Gastrointestinal Issues:** Esophageal tears, stomach problems. - **Lung Diseases:** Infections, pneumonia, pleurisy, pneumothorax, pulmonary embolism. - **Musculoskeletal Issues:** Common in the elderly, including shoulder diseases, arthritis, joint and muscle disorders. - **Pericardial Diseases:** Such as pericarditis. - **Tietze's Syndrome:** Costochondral junction inflammation, with localized tenderness upon touch.  - **Referred Pain:** Various conditions. - **Aortic Diseases:** Dissection, with symptoms very similar to coronary diseases, can even change ECG and cause infarction due to coronary involvement. **Major Chest Pain Conditions:** 1. Acute Coronary Syndrome (ACS) 2. Aortic Dissection 3. Pulmonary Embolism 4. Pneumothorax 5. Emotional and Anxiety Disorders (most common in young individuals) **Important Myocardial Ischemia Symptoms:** 1. **Silent Ischemia:** 5% of patients have no symptoms. 2. **Angina:** The most common symptom. 3. **Angina Equivalent:** Shortness of breath during walking without chest pain, and weakness while walking. **Plaque Rupture:** Even small, asymptomatic plaques can rupture due to activities like playing football. Diabetic patients with fatty plaques are more susceptible. Less common in smokers. Plaques with thin, fibrous caps are more prone to rupture, as are plaques in males and those with high LDL levels. **Acute Chest Pain in Patients:**  1. **ACS:** Most crucial. 2. **Aortic Dissection** 3. **Pulmonary Embolism** 4. **Pneumothorax** 5. **Tension Pneumothorax** 6. **Lung Rupture** **ECG Presentation:** - **Symptoms:** Central chest pain relieved by TNG, lasting 15-20 minutes, accompanied by nausea and vomiting. - **ACS Initial Diagnosis:** No ST elevation, negative T-wave, negative AVF, clinical changes in lateral and inferior leads. - **Troponin Test:** - Positive: Stable Myocardial Infarction/Non-ST Elevation Myocardial Infarction (NSTEMI) - Negative: Unstable Angina **Case 2:** **Patient:** Female with central chest pain radiating to the neck, worsening with walking, accompanied by nausea and vomiting, no history of gastrointestinal disease. **Initial Diagnosis:** Acute Coronary Syndrome (ACS) without ST elevation. **Troponin Test:** - **Unstable Angina:** Negative troponin. - **Non-ST Elevation MI (NSTEMI):** Positive troponin. **Cardiac Cell Resilience:** Cells can tolerate ischemia for over 20 minutes. **Diagnostic Steps:** 1. **History Taking:** First step to diagnose the condition. 2. **Clinical Examination:** To rule out other causes and proceed with further diagnostic methods if pointing towards ACS. 3. **ECG:** Initial ECG shows no ST elevation. If ST segment elevation is observed in adjacent leads, it’s classified as STEMI. If anginal symptoms are present without ST changes, it could be NSTEMI or MI. 4. **Cardiac Enzymes:** In ischemic or necrotic heart tissue, myocardial cell enzymes in the blood increase. Positive enzyme results (around 3-4 hours) confirm NSTEMI or MI, with ST changes ruling out STEMI. **Non-Specific Enzymes:** - **Creatine Kinase (CK) or Creatine Phosphokinase (CPK):** - **MB:** Predominantly in skeletal muscles, elevated with intense exercise. - **BB:** Elevated with stroke, also found in smooth muscles of the gut (e.g., peptic ulcer can elevate this enzyme). - **MB (CPK-MB):** More specific but also present in smooth muscle tissues of the gastrointestinal system, etc. **Cardiac Troponin:** The most specific enzyme for cardiac disorders. Elevated levels indicate myocardial cell damage, which could result from trauma, inflammation, or metastasis. - **Pulmonary Embolism:** Right ventricular strain and cellular damage release troponin. - **Kidney Damage:** Impaired troponin excretion raises blood levels, even without heart failure. **Diagnosing MI in Renal Failure Patients:** 1. **Echocardiography:** Can detect ventricular akinesia (lack of movement) but can't differentiate between old and new damage. 2. **CPK-MB:** Also useful but less specific than troponins. **Cardiac Troponin Types:** 1. **Troponin I:** Most specific and smallest. 2. **Troponin C** 3. **Troponin T** **Elevated Levels:** Troponins typically rise 3-4 hours after chest pain onset, peak, and remain elevated for about two weeks. False positives can occur in heart failure, pulmonary embolism, myocarditis, and renal impairment, especially affecting troponin I. **Echocardiography:** Identifies ischemia by reduced wall movement compared to other heart walls, but enzyme analysis is still required for MI diagnosis. **Stress Test:** Increases myocardial demand to check for symptoms, performed in two ways: 1. **Exercise Stress Test:** Uses exercise to stress the myocardium and monitors with ECG. 2. **Pharmacologic Stress Test:** For patients unable to exercise (e.g., spinal injury, elderly). Uses drugs and thallium imaging to detect ischemic areas. **First 24 Hours Post-ACS:** Stress tests aren't done in the first 24 hours. If clinical symptoms normalize and troponin levels don't elevate within 6 hours, the test can be performed. **CT Angiography:** This method visualizes coronary artery anatomy, stenosis, and wall calcifications. **Angiography:** The gold standard for diagnosis. Usually performed via the femoral artery (more routine), but also possible through the radial or brachial artery to directly inject contrast into the coronary arteries. **Treatment:** After diagnosis, we move to treatment, linked to pathophysiology: **STEMI:** A feeding artery is completely blocked, causing a transmural myocardial infarction. The primary treatment is to restore perfusion as quickly as possible (using thrombolytic drugs or angioplasty) and then proceed with other treatments. **NSTEMI:** Perfusion isn't completely cut off, indicating a non-transmural myocardial infarction. **Medication Treatments:** **1. Decreased Demand:** - **Rest:** Provide rest to reduce stress. - **Sedatives:** Lower stress and anxiety. - **Control Heart Rate:** Beta-blockers help lower demand. - **Preload Reduction:** Control systolic wall tension with venous vasodilators and nitrates. **2. Increased Supply:** - **Vasodilation:** Use nitrates in various forms (injection, oral, sublingual). Sublingual nitroglycerin (TNG) is a coronary vasodilator, helping to increase supply by relieving vessel spasm. - **Oxygen:** Administer oxygen to enhance oxygen-carrying capacity if needed. **3. Antiplatelets:** - **Aspirin:** The primary antiplatelet drug to prevent platelet aggregation. Various types exist, tailored to specific needs. Aspirin, at 160 mg, is a simple yet effective antiplatelet drug, inhibiting cyclooxygenase to reduce thromboxane A2 in platelets, preventing aggregation. It's crucial in ACS to lower mortality and recurrent MI risk, unless there's an aspirin allergy, then other antiplatelets are used. **Clopidogrel (Plavix):** A newer antiplatelet at 300 mg, blocking the P2Y12 receptor, stabilizing the platelet membrane, reducing aggregation. Other drugs in this category include IIb/IIIa inhibitors, which completely paralyze platelets, preventing aggregation. **Anticoagulants:** Prevent clot formation post-platelet aggregation, with heparin as the primary drug, available as unfractionated (normal) and fractionated (low molecular weight), with LMW being more specific. **Anti-Lipid Drugs:** Statins control LDL, taking time to lower levels but provide early anti-inflammatory effects, stabilizing endothelial cells and improving function, key in ACS management. **Remodeling Effect:** Ischemic myocardium leads to compensatory changes in surrounding tissues, causing left ventricular geometric changes. Initially beneficial, but excessive remodeling needs control, with ACE inhibitors like captopril and the diuretic spironolactone being effective. Beta-blockers and some calcium channel blockers also reduce myocardial demand, especially in high heart rate patients. **Non-Pharmacological Treatments:** **Percutaneous Coronary Intervention (PCI):** Also known as angioplasty, a balloon is placed at the atherosclerotic plaque site, breaking and crushing the plaque to open the lumen. A metal scaffold (stent), often drug-coated, is then placed to keep the lumen open and prevent fibroblast regrowth and restenosis. Post-PCI, patients must take antiplatelet drugs for at least 12 months to prevent clot reformation. **Coronary Artery Bypass Graft Surgery (CABGS):** In this open-heart surgery, a surgeon removes a vein from the leg (saphenous vein), closes all its side branches, and forms it into a tube. One end is attached to the aorta and the other past the site of narrowing, restoring blood flow. **Palliative Nature:** Both treatments are palliative, reducing symptoms but not curing the underlying disease. The primary treatment involves managing risk factors and halting or delaying atherosclerosis progression with medications.