Cardiovascular Pathophysiology Lecture 2 PDF

Pathophysiology Lecture 2 Cardiovascular Pathophysiology Ahmed E. Amer Ph.D. Pharmacology & Toxicology MSc Pharmacology & Toxicology Master of Clinical Nutrition Summer 2024  Introduction The cardiovascular s...

Pathophysiology Lecture 2 Cardiovascular Pathophysiology Ahmed E. Amer Ph.D. Pharmacology & Toxicology MSc Pharmacology & Toxicology Master of Clinical Nutrition Summer 2024  Introduction The cardiovascular system begins its activity when the fetus is 1 month old, and it’s the last system to cease activity at the end of life. The heart, arteries, veins, and lymphatics make up the cardiovascular system. These structures transport life-supporting oxygen and nutrients to cells, remove metabolic waste products, and carry hormones from one part of the body to another. Circulation requires normal heart function, which propels blood through the system by continuous rhythmic contractions. cardiovascular disease remains the leading cause of death. Heart attack, or myocardial infarction (MI), is the primary cause of cardiovascular-related deaths  Risk factors Modified risk factors Nonmodifiable risk factors ✓ Elevated serum lipid levels ✓ Age Susceptibility to cardiovascular disease increases ✓ Hypertension with age; disease before age 40 is unusual ✓ Cigarette smoking ✓ Male gender An estrogen effect? Women are less susceptible ✓ Diabetes mellitus than men to heart disease until after menopause; ✓ Sedentary lifestyle then they become as susceptible as men. ✓ Stress One theory proposes that estrogen has a protective effect ✓ Obesity (especially abdominal) ✓ Family history A positive family history also increases a person’s chances of developing premature cardiovascular disease. ✓ Race  Cardiovascular disorders The disorders discussed in this section include: o Cardiac tamponade o Cardiogenic shock o Coronary artery disease (CAD) o Myocardial Infarction (MI) o Heart failure o Hypertension (HTN)  Cardiac tamponade In cardiac tamponade, a rapid rise in intrapericardial pressure → impairs diastolic filling of the heart. The rise in pressure usually results from blood or fluid accumulation in the pericardial sac. In cardiac tamponade, the progressive accumulation of fluid in the pericardium → causes compression of the heart chambers. This ↓ blood flow into the ventricles and ↓ the amount of blood that can be pumped out of the heart with each contraction.  Cardiac tamponade (Cont.)  Reduced cardiac output → may be fatal without prompt treatment.  The amount of fluid necessary to cause cardiac tamponade varies greatly. It may be as  Small as 200 ml when the fluid accumulates rapidly  More than 2,000 ml if the fluid accumulates slowly.  If the condition is left untreated, cardiogenic shock and death can occur.  Cardiac tamponade (Cont.) Causes Cardiac tamponade may result from: Effusion, such as in cancer, bacterial Hemorrhage from nontraumatic infections, tuberculosis and, rarely, causes, such as rupture of th heart acute rheumatic fever or great vessels and anticoagulant Hemorrhage caused by trauma, such therapy as a gunshot or stab wound in the Chronic renal failure during dialysis chest, cardiac surgery, or perforation by a catheter during cardiac or central venous catheterization and pacemaker insertion  Cardiogenic shock  Sometimes called pump failure, cardiogenic shock is a condition of diminished cardiac output that severely impairs tissue perfusion as well as oxygen delivery to the tissues.  It reflects severe left-sided heart failure and occurs as a serious complication in some patients hospitalized with acute MI.  Cardiogenic shock typically affects patients whose area of infarction exceeds 40% of the heart’s muscle mass. In these patients, mortality may exceed 85%.  Most patients with cardiogenic shock die within 24 hours of onset. The prognosis for those who survive is extremely poor.  Cardiogenic shock (Cont.) How it Happens? 1. Left Ventricular Dysfunction: The underlying issue triggers compensatory mechanisms. 2. Compensatory Mechanisms: Aim to increase cardiac output and maintain vital organ function. 3. Baroreceptors Activation: As cardiac output falls, baroreceptors in the aorta and carotid arteries initiate responses in the sympathetic nervous system. 4. Sympathetic Responses: These responses increase heart rate, left ventricular filling pressure, and peripheral resistance to enhance venous return to the heart.  Cardiogenic shock (Cont.) A Vicious Cycle 1. Initial Stabilization: The compensatory responses initially stabilize the patient. 2. Deterioration: The patient later deteriorates as the oxygen demands of the already compromised heart rise. 3. Cycle of Deterioration: The events comprise a vicious cycle of low cardiac output, sympathetic compensation, myocardial ischemia, and even lower cardiac output.  Cardiogenic shock (Cont.) Symptoms Cardiogenic shock produces signs of poor tissue perfusion, such as:  Cold, pale, clammy skin  Rapid, shallow respirations  Drop in systolic blood pressure to 30  Oliguria (urine output less than 20 mm hg below baseline or a sustained ml/hour) reading below 80 mm hg that isn’t  Restlessness attributable to medication  Confusion  Weak peripheral pulses  Narrowing pulse pressure  Tachycardia  Atherosclerosis It is caused by deposition of plasma lipids (plaques) in the wall of the arteries  Since plasma is an aqueous medium → plasma lipids are present in combination with proteins in a water-soluble form (lipoproteins).  The deposited lipids include low density lipoproteins (LDL = the bad cholesterol) & very low density lipoproteins (VLDL).  High density lipoprotein (HDL or the good cholesterol) prevents deposition of other types of plasma lipids in the arteriolar walls.  Deposition of plasma lipids in arteriolar wall occur when their level in plasma is higher than normal called hyperlipidemia (when the bad lipids level is high) or hypercholesterolemia (when the cholesterol level is high).  Hyperlipidemia may be due to lifestyle (high-fat diet and sedentary life), drugs (β-blockers, oral contraceptives), or genetics.  Atherosclerosis (Cont.) 1. Tissue ischemia due to  blood flow. 2. Aneurysm or bleeding due to weakening of arteriolar walls. 3. Breaking- off atherosclerotic plaque to form ➔ travelling emboli Manifestations N.B Atherosclerosis results in hypertension due to the increased vascular resistance (peripheral resistance) due to loss of elasticity of the arterioles. Untreated hypertension leads to heart failure and death. 1. Elevated serum levels of LDL 2. Low serum levels of HDL 3. Familial history of hyperlipidemia or atherosclerotic disease Risk Factors 4. Smoking 5. Hypertension 6. Age: > 45 years in males & > 55 years in females 7. Drugs: β -blockers, oral contraceptives Steps in the Development of Atherosclerosis Monocytes enter area Endothelial injury of injury and release (examples: Infiltration of cholesterol growth factors that hypertension, immune molecules into blood stimulate smooth response, toxins in vessel walls. muscle and endothelial cigarette smoke, etc.). cell proliferation. Platelets adhere to the Monocytes phagocytize endothelial lesion; lipoproteins and fibroblasts infiltrate area Calcification of plaques become lipid- filled and cause progressive may occur over time. "foam cells." sclerosis or hardening of tissue. Significant narrowing of the blood vessel lumen can occur over time.  Coronary artery disease (CAD)  Coronary artery disease causes the loss of oxygen and nutrients to myocardial tissue because of decreased coronary blood flow.  Atherosclerosis is the most common cause of CAD.  In this condition, fatty, fibrous plaques, possibly including calcium deposits, progressively narrow the coronary artery lumens, which reduces the volume of blood that can flow through them.  This can lead to myocardial ischemia (a temporary deficiency of blood flow to the heart) and eventually necrosis (heart tissue death or myocardial infarction).  Coronary artery disease (Cont.) Risk factors Age > 40 Smoking (risk dramatically drops Male within 1 year of quitting) Hypertension (systolic blood pressure Stress greater than 140 mm Hg or diastolic Obesity, which increases the risk of blood pressure greater than 95 mm diabetes mellitus, hypertension, and Hg) high cholesterol Increased low-density and decreased Diabetes mellitus high-density lipoprotein levels  Coronary artery disease (Cont.) Pathophysiology ▪ As atherosclerosis progresses → luminal narrowing is accompanied by vascular changes that impair the diseased vessel’s ability to dilate. ▪ This causes an imbalance between myocardial oxygen supply and demand, threatening the myocardium beyond the lesion (↑ demand and ↓ supply). ▪ When oxygen demand exceeds what the diseased vessels can supply, localized myocardial ischemia results.  Coronary artery disease (Cont.) Pathophysiology ▪ Transient ischemia → ↓ myocardial function. If untreated, it can lead to tissue injury or necrosis. ▪ Oxygen deprivation forces the myocardium to shift from aerobic to anaerobic metabolism. o As a result, lactic acid (the end product of anaerobic metabolism) accumulates and reduces cellular pH with each contraction o The combination of hypoxia, reduced energy availability, and acidosis rapidly impairs left ventricular function.  Coronary artery disease (Cont.) Disorganized hemodynamic 1. Depression of left ventricular function → ↓ stroke volume and ↓ cardiac output. 2. Decrease in systolic emptying → ↑ ventricular volumes. 3. Left-sided heart pressures and pulmonary pressure ↑. 4. A sympathetic response o During ischemia, sympathetic nervous system response → ↑ blood pressure and ↑ heart rate before the onset of pain. o With the onset of pain, further sympathetic activation occurs leading to further deterioration.  Coronary artery disease (Cont.) 1. 2. Imbalance in 3. Localized Atherosclerosis Oxygen Supply Myocardial Progression and Demand Ischemia Pathophysiology 6. Lactic Acid 5. Oxygen 4. Transient Accumulation Deprivation Ischemia 8. Impaired Left 7. Reduced Ventricular Cellular pH Function  Coronary artery disease (Cont.) 1. Reduced Contractility and Impaired Wall Motion Disorganized hemodynamic 2. Depression of Left Ventricular Function 3. Decrease in Systolic Emptying 4. Increase in Left-sided Heart Pressures and Pulmonary Pressure 5. Sympathetic Response 6. Onset of Pain and Further Sympathetic Activation 7. Further Deterioration  Coronary artery disease (Cont.)  Angina is the classic sign of CAD.  The patient may describe a burning, squeezing, or crushing tightness in the substernal or precordial area that radiates to the left arm, neck, jaw, or shoulder blade. He may clench his fist over his chest or rub his left arm when describing it. Pain is commonly accompanied by nausea, vomiting, fainting, sweating, and cool extremities.  Angina commonly occurs after physical exertion but may also follow emotional excitement, exposure to cold, or the consumption of a large meal.  Sometimes, it develops during sleep and awakens the patient.  Coronary artery disease (Cont.) When to label it stable or unstable? If the pain is predictable and relieved by rest or nitrates, it’s called stable angina.  If it increases in frequency and duration and is more easily induced, it’s called unstable or unpredictable angina.  Heart Failure When the myocardium can’t pump effectively enough to meet the body’s metabolic needs, heart failure occurs. Pump failure usually occurs in a damaged left ventricle, but it may also happen in the right ventricle. Heart failure may be classified in different ways according to its pathophysiology as Right-Sided or Left-Sided.  Left-Sided Heart Failure It occurs due to ineffective left ventricular contractile function, leading to:  Pulmonary congestion or pulmonary edema.  Decreased cardiac output.  Fluid accumulation backing up into the left atrium and then into the lungs, which may result in pulmonary edema and right-sided heart failure.  Left-Sided Heart Failure (Cont.) Pathophysiology 1- Increased Workload: Increased workload enlarges the left ventricle. The ventricle enlarges with stretched tissue rather than functional tissue due to lack of oxygen. Symptoms: Increased heart rate, pale and cool skin, tingling in extremities, decreased cardiac output, and arrhythmias. 2- Decreased Ventricular Function: Decreased left ventricular function allows blood to pool in the ventricle and atrium, eventually backing up into the pulmonary veins and capillaries.  Left-Sided Heart Failure (Cont.) Pathophysiology 3- Impaired Pulmonary Circulation: Swollen pulmonary circulation increases capillary pressure, pushing sodium and water into the interstitial space, and causing pulmonary edema. Symptoms: Coughing, crackles, tachypnea, increased pulmonary artery pressure, decreased pulmonary compliance. 4- Worsened Pulmonary Edema: When the patient lies down, fluid in the extremities moves into the systemic circulation. The left ventricle can’t handle the increased venous return, causing fluid to pool in the pulmonary circulation, worsening pulmonary edema. 5- Progression to Right-Sided Heart Failure: The right ventricle becomes stressed due to greater pulmonary vascular resistance and left ventricular pressure, worsening symptoms.  Left-Sided Heart Failure (Cont.) Pathophysiology 5- 2- 4- 1- 3- Impaired Progression Decreased Worsened Increased Pulmonary to Right- Ventricular Pulmonary Workload Circulation Sided Heart Function Edema Failure  Right-Sided Heart Failure  It occurs due to ineffective right ventricular contractile function.  Causes include acute right ventricular infarction or pulmonary embolus, but the most common cause is profound backward flow due to left-sided heart failure. Pathophysiology 1- Stretched Tissue Formation: The stressed right ventricle enlarges, forming stretched tissue and increasing conduction time, leading to arrhythmias. Symptoms: Increased heart rate, cool skin, cyanosis, decreased cardiac output, palpitations, and dyspnea.  Right-Sided Heart Failure (Cont.) Pathophysiology 2- Decreased Right Ventricular Function: Blood pools in the right ventricle and right atrium. Backed-up blood causes pressure and congestion in the vena cava and systemic circulation. Systemic congestion results in increased central venous pressure, jugular vein distention, and hepatojugular reflux. Distention of visceral veins (hepatic vein) causes liver and spleen swelling, impairing their function. Symptoms: Anorexia, nausea, abdominal pain, palpable liver and spleen, weakness, and dyspnea secondary to abdominal distention.  Right-Sided Heart Failure (Cont.) Pathophysiology 3- Increased Capillary Pressure: Increased capillary pressure forces excess fluid from capillaries into the interstitial space, causing tissue edema, especially in the lower extremities and abdomen. Symptoms: Weight gain, pitting edema, and nocturia.  Heart Failure Risk Factors Arrhythmias: Infections: Tachyarrhythmias: Decreased ventricular Increased metabolic demands, further filling time. burdening the heart. Bradycardia: Decreased cardiac output. Anemia: Pregnancy and thyrotoxicosis. Increased cardiac output to meet the Pulmonary embolism: oxygen needs of tissues. Increased pulmonary pressure, leading to Increased physical activity. right-sided heart failure. Increased salt or water intake. Emotional stress.  Myocardial Infarction (MI)  MI is an acute coronary syndrome resulting from reduced blood flow through one of the coronary arteries.  This causes myocardial ischemia, injury, and necrosis.  MI results from occlusion of one or more of the coronary arteries.  Occlusion could be due to atherosclerosis, thrombosis, platelet aggregation, or coronary artery stenosis or spasm.  Myocardial Infarction (MI) (Cont.) Risk Factors Aging Hypertension Diabetes mellitus Obesity Increased serum triglyceride, low- Positive family history of CAD density lipoprotein, cholesterol, and Smoking decreased serum high-density Stress lipoprotein levels Use of amphetamines or cocaine Increased intake of saturated fats, carbohydrates, or salt  Myocardial Infarction (MI) (Cont.) Pathophysiology Injury to the endothelial lining of the coronary arteries leads to accumulation of platelets, white blood cells, fibrin, and lipids at the 1-Injury of Coronary Blood injured site. Vessels: Foam cells, or resident macrophages, gather under the damaged lining, absorb oxidized cholesterol, and form fatty deposits, narrowing the arterial lumen. 2- Collateral Circulation As the arterial lumen narrows gradually, collateral circulation develops, Formation: helping to maintain myocardial perfusion distal to the obstruction. Increased myocardial demand for oxygen surpasses the collateral circulation supply, leading to increased anaerobic metabolism and 3- Anaerobic Metabolism: lactic acid production. Lactic acid stimulates nerve endings.  Myocardial Infarction (MI) (Cont.) Pathophysiology Decreased oxygen supply causes myocardial cells to die, resulting in 4- Cardiomyocyte Death: decreased contractility, stroke volume, and blood pressure. Hypoperfusion increases baroreceptor activity, stimulating the 5- Baroreceptor Reflex: adrenal glands to release epinephrine and norepinephrine. Increased catecholamines raise heart rate and cause peripheral vasoconstriction, increasing myocardial oxygen demand Damaged cell membranes in the infarcted area release intracellular contents into the vascular circulation. 6- Ventricular Arrhythmias: Elevated serum potassium, cardiac troponin, and creatinine kinase levels lead to ventricular arrhythmias.  Myocardial Infarction (MI) (Cont.) Pathophysiology All myocardial cells are capable of spontaneous depolarization 7- Formation of Ectopic Foci: and repolarization, so the electrical conduction system may be affected by infarct, injury, and ischemia. 8- Increased Pulmonary Extensive damage to the left ventricle decreases its ability to Pressure pump, causing blood to back up into the left atrium and subsequently into the pulmonary veins and capillaries. Crackles may be heard in the lungs on auscultation, and pulmonary artery pressures are increased. Increased back pressure causes fluid to cross the alveolocapillary 9- Impaired Pulmonary Function membrane, decreasing diffusion of oxygen (O2) and carbon dioxide (CO2).  Myocardial Infarction (MI) (Cont.) Pathophysiology 1-Injury of 2- Collateral 3- Anaerobic Coronary Blood Circulation Metabolism Vessels Formation 4- 5- Baroreceptor 6- Ventricular Cardiomyocyte Reflex Arrhythmias Death 8- Increased 9- Impaired 7- Formation of Pulmonary Pulmonary Ectopic Foci Pressure Function  Hypertension Hypertension is an intermittent or sustained elevation of diastolic or systolic blood pressure. A sustained systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher indicates hypertension. Types of Hypertension Essential (Primary) hypertension Secondary hypertension: The etiology is complex and involves several Related to a systemic disease that raises interacting homeostatic mechanisms. peripheral vascular resistance or cardiac It usually begins insidiously as a benign disease output. but can cause major complications and death if left untreated. Note Malignant hypertension: A severe, fulminant form that may arise from either type.  Hypertension (Cont.) Causes of Hypertension Increases in cardiac output Increases in peripheral resistance Cardiac output is increased by conditions that Peripheral resistance is increased by factors increase heart rate or stroke volume that increase blood viscosity or reduce the lumen size of vessels, especially the arterioles. Contributing factors ✓ Family history ✓ Use of tobacco or hormonal ✓ Race contraceptives ✓ Stress ✓ A sedentary lifestyle ✓ Obesity ✓ Aging ✓ A diet high in fat or sodium  Theories Explaining Hypertension Development Hypertension is thought to arise from: Changes in the arteriolar bed, causing increased resistance. Abnormally increased tone in the sensory nervous system that originates in the vasomotor system centers, causing increased peripheral vascular resistance. Increased blood volume resulting from renal or hormonal dysfunction An increase in arteriolar thickening caused by genetic factors, leading to increased peripheral vascular resistance. Abnormal renin release resulting in the formation of angiotensin II, which constricts the arterioles and increases blood volume.  Pathophysiology of Secondary Hypertension The pathophysiology of secondary hypertension is related to the underlying disease: The most common cause of secondary hypertension. Chronic kidney disease Insult to the kidney from chronic glomerulonephritis or renal artery stenosis interferes with sodium excretion, the renin-angiotensin-aldosterone system, or renal perfusion, causing blood pressure to rise Increased cortisol levels raise blood pressure by increasing renal sodium Cushing’s syndrome retention, angiotensin II levels, and vascular response to norepinephrine. Increased intravascular volume, altered sodium concentrations in vessel walls, or Primary aldosteronism very high aldosterone levels cause vasoconstriction (increased resistance). A secreting tumor of chromaffin cells, usually of the adrenal medulla. Causes hypertension due to increased secretion of epinephrine and norepinephrine. Pheochromocytoma Epinephrine increases cardiac contractility and rate. Norepinephrine increases peripheral vascular resistance.  Late Complications of hypertension ✓ CAD ✓ Angina ✓ MI Cardiac complications ✓ Heart failure ✓ Arrhythmias ✓ Sudden death ✓ Stroke Neurologic complications: ✓ Hypertensive encephalopathy Hypertensive retinopathy ✓ Can cause blindness Renovascular ✓ Can lead to renal failure hypertension  Effects of Hypertension on the Heart Hypertension increases the heart’s workload, causing: Left ventricular hypertrophy Later, left-sided heart failure Pulmonary edema Right-sided heart failure