NUR 201 Final Study Guide PDF

**NUR 201 FINAL STUDY GUIDE** **[Cardiac System:]** **[Anatomical Structures of the Heart:]** Blood Flow Through the Heart **Deoxygenated Blood Flow**: - Blood returns to the **right atrium** via the **superior** and **inferior vena cava**. - From the right atrium, blood flows through...

**NUR 201 FINAL STUDY GUIDE** **[Cardiac System:]** **[Anatomical Structures of the Heart:]** Blood Flow Through the Heart **Deoxygenated Blood Flow**: - Blood returns to the **right atrium** via the **superior** and **inferior vena cava**. - From the right atrium, blood flows through the **tricuspid valve** into the **right ventricle**. **Pulmonary Circulation**: - The right ventricle contracts, pushing blood through the **pulmonary valve** into the **pulmonary arteries**. - Blood travels to the lungs, where it undergoes gas exchange **Oxygenated Blood Flow**: - Oxygenated blood returns to the **left atrium** via the **pulmonary veins**. - Blood moves from the left atrium through the **mitral valve** into the **left ventricle**. **Systemic Circulation**: - The left ventricle contracts, pushing blood through the **aortic valve** into the **aorta**. - Blood is then distributed throughout the body, delivering oxygen and nutrients to tissues and organs. **[The heart is composed of 3 layers]**: the **endocardium, the myocardium, and the epicardium**. - The epicardium is surrounded by the pericardium: the **visceral pericardium and the parietal pericardium.** - The heart muscle is on the left. The skeletal muscle is on the right. - **test question** - **Excitation contraction coupling** occurs in the muscle (both heart and skeletal). It is the electrical current and generation of an action potential in combination with a physical contraction component. - In heart muscle, nodal cells release an action potential that sets off a calcium induced calcium release through interrelated gap junctions, so the entire muscle contracts in unison - In skeletal muscle, the nerves synapse into the muscle cell. To have fine motor control all muscles do not contract together - The heart muscle has one nucleus, and the skeletal muscle has multiple nuclei. - Nuclei are involved in protein synthesis, and you need multiple in skeletal muscle to speed up proteins synthesis for use and repair of the muscle. - Cardiac muscle is an example of a **functional syncytium**. Individual cells are connected by gap junctions, which allow for the transfer of ions and electrical energy through the muscle. This ensures the muscle fibers can contract at the same time, allowing the heart to beat as one unit. - Skeletal muscle is a **true syncytium** **[Coronary Circulation: ]** They originate from the aorta and are divided primarily into two main arteries: the left coronary artery (LCA) and the right coronary artery (RCA). - The coronaries are found in the epicardium and send branches inward to perfuse the myocardium. They are perfused during diastole. - The LCA branches into the Left Anterior Descending Artery (LAD) and the Left Circumflex Artery (LCx). - The RCA branches into the Right Marginal Artery and the Posterior Descending Artery (PDA)  **Left Coronary Artery (LCA)**.  - Left Anterior Descending Artery (LAD) - **Anterior wall of the left ventricle** - The **interventricular septum** - Some of the lateral wall of the LV - An occlusion of the LAD causes and **anterior wall infarction.** - **EKG Findings**: ST elevation in V1-V4, ST depression in reciprocal leads II, III, and aVF - V1 and V2 are septal leads - V3 and V4 are anterior leads - **Complications**: - **Heart failure** - Cardiogenic shock - Pulmonary edema - Left ventricular dysfunction - **Ventricular septal defect or rupture** - Presents with new murmur and HF - Conduction abnormalities, including a type II heart block or RBBB since the LAD supplies the bundle of his. - **Creation of reentrant circuits that can lead to VT or VF** - Pericarditis - Free wall infarct free wall rupture cardiac tamponade - Pseudoaneurysm that leads to clots and can causes thromboemboli. - Left Circumflex Artery (LCx) - The LCx supplies the **lateral and posterior walls of the left ventricle**. - Occlusion of the circumflex artery causes **lateral or posterior wall infarction** - **EKG Findings**: ST elevation in V5 and V6 (low lateral) or I and aVL (high lateral) - Lateral leads - **Complications:** - While less common than LAD infarctions, circumflex artery blockages can still lead to significant heart dysfunction. Posterior infarctions are often associated with right ventricular involvement, leading to complications like hypotension and arrhythmias. - **Creation of reentrant circuits that can lead to VT or VF** - pericarditis **Right Coronary Artery (RCA)** - The RCA supplies the right ventricle, the inferior wall of the left ventricle, and the posterior part of the interventricular septum. - Occlusion of the RCA causes **inferior wall infarction**. - **EKG Findings:** ST elevations in II, III, aVF, reciprocal changes in lateral wall I and aVL. - Inferior leads - **Complications:** - SA and AV conduction disturbances: second degree type I heart block, third degree heart block, SSS, SB - **AV block and Bradycardia** - **Mitral valve regurgitation** secondary to **papillary muscle rupture** - Presents with new murmur and HF - Pericarditis - RCA blockages may cause less severe reductions in cardiac output than LAD blockages but still present risks like right ventricular failure and arrhythmias. - Use beta blockers and NTG with caution - **Right Marginal Artery** - **Posterior Descending Artery (PDA)** - **The posterior portion of the heart** - Some parts of right and left ventricle - **Right Ventricular Infarct** - a type of inferior MI of RCA occlusion. - The RCA also supplies the RV - A right sided EKG will demonstrate **ST changes in V4R** - Signs and symptoms: - JVD, high CVP, hypotension, clear lungs, bradyarrythmias - Avoid preload reducers like nitrates and diuretics and caution with beta blockers **Dominance** - The distribution of the coronary arteries can vary, leading to classifications of \"right dominance,\" \"left dominance,\" or \"codominance,\" depending on which artery gives rise to the PDA. In right dominance (most common), the RCA supplies the PDA; in left dominance, the LCx does. Most people are right dominant. ### **[Pathophysiology of Acute Myocardial Infarction:]** ### effects but be seen in contiguous leads (two or more). - ### T wave inversions are the first sign of strain on the heart, ST depressions are a sign of ischemia, ST elevation is a sign of infarct, pathological Q waves are a sign of an old infarct 1. **Atherosclerosis and Plaque Rupture**: - **Atherosclerosis**: Over time, cholesterol, fatty deposits, and other substances build up on the walls of coronary arteries, forming plaques. These plaques narrow the arteries and reduce blood flow. - SADCHF: Smoking, advanced age, DM, Cholesterol (high LDL, low HDL), HTN, family hx of CAD - **Plaque Rupture and Thrombosis**: In acute MI, the atherosclerotic plaque in the coronary artery often ruptures or erodes. This triggers the formation of a thrombus at the site of rupture. The clot further obstructs the blood flow, and if it completely occludes the artery, it causes a myocardial infarction. 2. **Ischemia and Cellular Injury**: - The lack of blood flow to the heart muscle deprives it of oxygen and nutrients. This results in ischemia, and after a few minutes, irreversible injury to the heart muscle begins. Initially, the heart muscle cells suffer metabolic disturbances (e.g., decreased ATP production, increased lactic acid). As ischemia persists, the myocardial cells begin to die, leading to infarction (irreversible tissue damage). - STEMI results in total occlusion of blood supply and no oxygen supply. Troponins will be elevated and ST elevations present on EKG. 3. **Infarction and Necrosis**: - The affected area of the heart muscle undergoes necrosis, where the cells die. This process begins at the subendocardial region and can extend to the epicardial surface if the blockage persists. - The myocardial tissue that undergoes necrosis is replaced by scar tissue, which does not contract like normal heart muscle, leading to a decrease in the heart\'s pumping efficiency. 4. **Inflammatory Response**: - The body activates an inflammatory response following tissue injury. Inflammatory cells, such as neutrophils and macrophages, migrate to the site of damage to remove dead tissue and facilitate healing. This inflammatory process can further contribute to heart dysfunction and arrhythmias. **[Summary:]** The rupture of an atherosclerotic plaque initiates an inflammatory response of monocytes and macrophages, leading to thrombus formation and platelet aggregation. This process decreases oxygen delivery through the coronary artery, resulting in inadequate oxygenation of the myocardium. The subsequent inability to produce ATP in the mitochondria triggers an ischemic cascade, ultimately leading to apoptosis of the endocardium or myocardial infarction. **[Cardiogenic Shock:]** - Caused by some pathology of the heart leading to decreased function (LVHF), such as MI, HF, and surgery. - Heart muscle dies, contractility decreased - In an attempt to increase vascular tone, a release of endogenous vasopressors such as norepinephrine may increase systemic vascular resistance, but still due to a hypokinetic heart, MAP remains low - Treatment - Inotropes, Vasopressors, assistive devices (ECMO, IABP, impella) - Hemodynamic Trends - CO decreased, SV decreased, Increased CVP/PA pressure, low MAP, increased SVR, HR increased **[Obstructive Shock: (*FORMATIVE)*]** - Cardiac tamponade is an example of obstructive shock. - The echocardiogram in the patient with severe cardiac tamponade would be expected to show a pericardial effusion and diastolic collapse of the right-sided chambers of the heart. - The pericardial effusion is the etiology for the significant external pressures experienced by the right atrium and ventricle. Under this pressure, the chambers collapse and are not able to fill, therefore their preload would be decreased. - This collapse is greatest when the chambers are most relaxed in diastole. **[Cardiac Parameters:]** - **Preload**: refers to the degree of **stretch** of the cardiac muscle fibers at the end of diastole, just before the heart contracts. It is influenced primarily by the volume of blood returning to the heart (venous return) and the filling pressure in the ventricles. Measured by CVP and LVEDP. - CVP: 2-6  - **Left ventricular end-diastolic pressure (LVEDP)** is the **pressure** in the left ventricle at the end of diastole, serving as a surrogate for preload. - 6 to 12 mm Hg. - **Afterload** is the resistance the left ventricle must overcome to eject blood, often represented by **systemic vascular resistance (SVR)**. - SVR: 800 to 1200 dyns·s·cm⁻⁵ The relationship between **cardiac output (CO)**, **systemic vascular resistance (SVR)**, and **blood pressure (BP)** is governed by the basic hemodynamic equation: BP=CO×SVR - **BP (Blood Pressure)** is the force exerted by the blood against the walls of the arteries as the heart pumps blood through the circulatory system. - **SVR (Systemic Vascular Resistance)** is the resistance the blood encounters as it flows through the small arteries and arterioles. It is influenced by the tone of the arterioles (vascular smooth muscle contraction) and the total cross-sectional area of the vascular bed. - **CO (Cardiac Output)** is the volume of blood the heart pumps per minute, which depends on the **stroke volume (SV)** and **heart rate (HR)**. Normal is 4-8 L/min. CO=SV×HR - **SV (Stroke Volume)** is the amount of blood ejected by the heart with each contraction, influenced by preload, afterload, and myocardial contractility. Normal is 60-100 ml/beat. - **HR (Heart Rate)** is the number of heart beats per minute. **[Hypertension:]** **Systolic BP:** the arterial pressure when the heart's contracting. **Diastolic BP:** the arterial pressure when the heart's relaxing or refilling. - Normal: Less than 120/80 - Elevated: 120-129 SBP, DBP \ 140/90 - Can have isolated systolic hypertension or isolated diastolic hypertension- when one number is normal and the other is high **Primary Hypertension**: no clear cause - Risk factors: old age, obesity, high sodium diet, sedentary lifestyle **Secondary Hypertension:** there is a clear cause - Diminished renal blood flow, atherosclerosis, vasculitis, aortic dissection, fibromuscular dysplagia **[Pathophysiology of Hypertension:]** ### 1. Genetic Factors - Family history plays a significant role in the development of hypertension, with multiple genes implicated in blood pressure regulation. ### 2. Neurohumoral Regulation - The sympathetic nervous system (SNS) can become overactive, leading to increased heart rate and vasoconstriction. - The renin-angiotensin-aldosterone system (RAAS) is crucial, where the kidneys release renin, converting angiotensinogen to angiotensin I, which is then converted by ACE into angiotensin II. This potent vasoconstrictor increases blood pressure and stimulates aldosterone secretion, causing sodium and water retention. ### 3. Vascular Factors - Endothelial dysfunction is common in hypertension, characterized by reduced nitric oxide availability, leading to impaired vasodilation and increased vascular resistance. - Arterial stiffness increases with age or in response to risk factors, contributing to elevated systolic blood pressure. ### 4. Kidney Function - The kidneys regulate blood pressure through volume control and the secretion of renin. In hypertension, there may be alterations in renal blood flow and nephron function. ### 5. Lifestyle Factors - Factors such as obesity, high sodium intake, physical inactivity, and excessive alcohol consumption can contribute to the development of hypertension. **[Hypertensive Crisis:]** - Acute hypertension with SBP \> 180 mmhg and/or DBP \> 120 mmhg - Causes: medication noncompliance, pregnancy (pre-eclampsia), renal disorder, secondary to other medications/illicit drugs - **Hypertensive Urgency:** no end organ damage - s/sx: headache, nosebleeds, dizziness, restlessness - **Hypertensive Emergency:** end organ damage - s/sx: AMS, vision changes, HF, MI, back pain (kidneys), abdominal pain (AAA) - End organ damage can include pulmonary edema, cardiac ischemia, neurologic deficits, acute renal failure, aortic dissection, and eclampsia. - The pathophysiology resulting in end-organ dysfunction in hypertensive emergencies is not fully understood. However, the mechanical stress on vascular walls likely leads to endothelial damage and a pro-inflammatory response. This results in increased vascular permeability, platelet, and coagulation cascade activation, and fibrin clot deposition leads to hypoperfusion at the level of the target organ tissue. - **Treatment Guidelines** 1. 2. 3. 4. **[Pulmonary edema]** - the accumulation of excessive fluid in the alveolar walls and alveolar spaces of the lungs. - can be cardiogenic (disturbed starling forces involving the pulmonary vasculature and interstitium) or non-cardiogenic (direct injury/damage to lung parenchyma/vasculature). - The cardiogenic form of pulmonary edema (pressure-induced) produces a non-inflammatory type of edema by the disturbance in **Starling forces**. Any factor that increases this pressure can cause pulmonary edema.  In a **hypertensive crisis**, blood pressure rises drastically, leading to changes in the forces that control fluid movement in the body, called **Starling forces**. These include: 1. **Capillary hydrostatic pressure (Pc)**: High blood pressure increases this pressure in the **pulmonary capillaries**, pushing fluid out of the capillaries and into the **lungs**. 2. **Capillary oncotic pressure (πc)**: A drop in plasma proteins (e.g., albumin) reduces the pull of fluid back into the capillaries, worsening fluid leakage into the lungs. 3. **Increased vascular permeability**: High pressure can damage the blood vessel walls in the lungs, allowing more fluid to leak out. 4. **Impaired lymphatic drainage**: The body\'s ability to clear fluid from the lungs is overwhelmed, leading to fluid accumulation. **[Electrical Conduction System:]** - **Sinoatrial (SA) Node**: The pacemaker of the heart, located in the **right atrium**, initiates electrical impulses that trigger heartbeats. The impulses spread through the atria, causing them to contract and push blood into the ventricles. - **Atrioventricular (AV) Node**: Located at the **junction of the atria and ventricles** **in the interatrial septum**. Receives impulses from the SA node and transmits them to the ventricles, allowing them to contract after the atria. There is a **slight delay** is crucial for ventricular filling. - **The only place where an electrical signal can go from the atria to the ventricles.** - **Bundle of His**: Extends from the AV node into **the interventricular septum**, dividing into right and left bundle branches. Conducts impulses from the AV node into the ventricle for **coordinated** ventricular contraction. - The left bundle branch further divides into the anterior and posterior fascicles. - **Purkinje Fibers:** spread throughout the **ventricular myocardium**, branching off from the bundle branches. Function to distribute the electrical impulse **quickly and evenly** throughout the ventricles. - **Bachmann's bundle**, is a direct connection between the right and left atrium so they can contract in unison. **Firing Rate:** - SA node: 60-100 per min - Other parts of atria: 60-80 per min - AV node: 40- 60 per min (Junctional rhythm) - Bundle of His/Purkinje fibers: 20-40 per min (Idioventricular rhythm) - SA node is the primary pacemaker. Other cells are considered an ectopic pacemaker. **Summary of the Pathway:** The conduction pathway starts with the SA node, which generates an impulse that travels through the atria to the AV node. The AV node delays the signal before passing it to the Bundle of His, which splits into the right and left bundle branches. Finally, the impulse travels through the Purkinje fibers, resulting in ventricular contraction. **[Depolarization and Repolarization:]** The heart\'s contractions are regulated by an electrical conduction system. The heart\'s conduction system is a specialized network of cardiac muscle cells responsible for generating and propagating electrical impulses that coordinate heartbeats. - The heart is made of **pacemaker cells and contractile (myocytes) cells.** - Action potentials are sent out by the pacemaker cells in the heart. They are **autorhythmic** and able to continually generate new **action potentials**. They set the rate and rhythm of the heart. - The myocytes receive action potentials from pacemaker cells and make up the **myocardium**. **[Pacemaker Cells Depolarization and Repolarization:]** - **Depolarization** occurs when the inside of cells goes from **negative to positive** and cause a contraction. - Cardiac depolarization is the process by which the heart\'s electrical system initiates and propagates electrical impulses, leading to coordinated myocardial contraction. - Resting potential of the cell membrane of pacemaker cells is -60. - They contain **funny Na+ channels** that are leaky and allow Na to slowly leak in. - When the Na leaks into the cell it becomes more positive and reaches a threshold of -40 it opens **voltage gated Ca+ channels** and Ca+ will slowly diffuse into the cell until the membrane charge reaches +10 and the Ca+ channels close. - **Repolarization** occurs when the inside cell goes from **positive to negative**. - K+ channels open at +10 and K+ leaks out of the cell and the cell again becomes negative inside. **[Action potential cycle of nodal cardiac myocyte:]** - **Phase 4**: **Slow depolarization** due to a mixed Na+ inward current (Funny current), K+ outward current, T-type calcium channels opening. - **Phase 0**: **Rapid depolarization** caused by a large influx of Ca²⁺ through L-type calcium channels. - **Phase 3**: **Repolarization** as K⁺ ions flow out and Ca²⁺ channels close. - Unlike other cardiac myocytes, the pacemaker cells do not have a stable resting membrane potential, but instead, they undergo a slow, spontaneous depolarization after each action potential. - Sympathetic stimulation causes the action potentials to occur faster, vagal stimulation causes it to happen slower (ex: carotid massage) **[Myocyte Cells Depolarization and Repolarization:]** - Contractile cells have a true resting membrane potential of -90. The threshold for excitability is about +10. - They receive action potentials through **gap junctions**. After pacemaker cells depolarize, Na+ and Ca+ travel down the concentration gradient into myocytes and depolarize them. - When the threshold of -70 is reached it will open fast Na+ channels and Na+ will rush into cells until they reach +10. The Na+ channels close and Ca+ channels and K+ channels open. - K+ leaks out and Ca+ slowly moves in. The cells also contain sarcoplasmic reticulum that contains large amounts of Ca+. The cell reaches an equilibrium and forms a plateau. - The Ca+ channels then close and K+ channels remain open and continues to leak out making the inside of the cell more negative. - Cardiac repolarization is the process by which the heart\'s muscle cells return to their resting state after depolarization, which is essential for the heart to prepare for the next contraction. This process involves the coordinated activity of various ion channels and currents. - **Phase 0: Depolarization.** Rapid Na+ influx through open fast Na+ voltage gated channels. - **Phase 1**: **Initial Repolarization.** Voltage-gated potassium channels open and K⁺ to exits the cell, which leads to a small drop in membrane potential. - **Phase 2**: **Plateau phase.** Balance between inward calcium currents through L-type calcium channels and outward potassium currents. - **Phase 3: Rapid repolarization.** Ca channels close and the outward flow of K⁺ continues, causing the membrane potential to repolarize toward the resting potential of -90 mV. - **Phase 4: Resting phase.** membrane potential is maintained by the inward rectifier potassium current, ensuring the cell is ready for the next action potential. Na/K ATPase pump maintains the resting gradient. Na and Ca channels are closed. - The **absolute refractory period** occurs during phases 0, 1, 2, and part of phase 3 of the cardiac action potential. During this period, the cardiac cells are completely unresponsive to any new stimulus, regardless of its strength. This is due to the inactivation of sodium channels, which prevents the initiation of another action potential. - The absolute refractory period is critical for the proper functioning of the heart, as it: prevents tetany and sustained contractions, helps avoid re-entry arrhythmias and ensures the heart\'s electrical activity is coordinated, maintains rhythm stability, ensuring efficient filling and contraction of the heart, protects against premature contractions (like PVCs), contributes to the timing and control of the cardiac action potential, and is important in the pharmacological treatment of arrhythmias - The **relative refractory period** follows the ARP and occurs during the latter part of phase 3 of the cardiac action potential. During the RRP, some sodium channels begin to recover from inactivation, and a **stronger-than-normal** stimulus can initiate another action potential. However, the response during this period is typically weaker and slower due to the incomplete recovery of the ion channels. - A patient with a prolonged QT is at risk for torsades and amiodarone and other medications that prolong the RRP, phase 3 of the action potential, should be avoided. Lidocaine would be more beneficial -- **test question**  **[Differentiate between the action potentials from three different cells (neuron, skeletal muscle, cardiac myocyte) *FORMATIVE*]** - The action potential for cardiac muscle is much longer than that for skeletal muscle. - Cardiac myocytes to have longer action potential durations than skeletal muscle because they require more time for chamber filling, valve opening and closing, chamber contraction. - Skeletal muscle has a shorter action potential because the skeletal muscle "resets" quickly, allowing for precise fine motor control and rapid activation/deactivation of muscle groups. Neurons need even shorter refractory periods to reset even faster. **[The conduction cycle related to an electrocardiogram (ECG) waveform:]** represents the sequence of electrical events that occur during a single heartbeat. The graph is represented with amplitude vs. time. This cycle can be broken down into several key components, each corresponding to specific phases of cardiac depolarization and repolarization: - The isoelectric line is the baseline - To be a regular rhythm there are 4 criteria that must be met: a P wave, a QRS for every P wave, a regular R-R interval, HR 60-100             1. **U wave**: Occasionally seen following the T wave, the U wave\'s origin is less well understood but is thought to be related to the repolarization of the Purkinje fibers or the late repolarization of the ventricles. **[Electrolyte Disturbances and their Effect on EKG and Action Potential: ]** Each electrolyte disturbance can cause changes in the **action potential** that affect **cardiac conduction**, **repolarization**, and **action potential duration**, ultimately leading to **ECG abnormalities**.  https://www.youtube.com/watch?v=Wip-A4ZkmiE **[Pressure Volume Loop:]** The pressure-volume loop represents the relationship between the pressure in the ventricles and the volume of blood they contain throughout the cardiac cycle. Each loop represents the physiology of the left ventricle throughout one cardiac cycle. It consists of four main phases: Starts at the end diastolic point. S1, when the mitral valve closes. LV is filled with a max amount of volume (EDV) so volume is high and pressure is low. 1. **Isovolumetric Contraction**: The ventricles contract, **increasing pressure without changing volume** (*all valves closed*). This phase ends when the aortic or pulmonary valve opens. Semilunar valves open due to higher pressure inside ventricles. 2. **Ejection Phase**: Blood is ejected from the ventricles into the aorta or pulmonary artery, **leading to a decrease in volume and a continued increase in pressure** until aortic/pulmonary valve closure. Semilunar valves close when the pressure is higher in the aorta than the ventricles. Sound is known as S2. 3. **Isovolumetric Relaxation**: The ventricles relax, and **pressure drops while volume remains constant** (*all valves closed*) until the mitral or tricuspid valve opens. The AVs open when LV pressure is lower than atrial pressure. 4. **Relaxation/Filling Phase**: Blood flows into the ventricles from the atria due to pressure gradient, increasing volume at low pressure until the ventricle is filled, preparing for the next contraction. #### **Key Points on Pressure-Volume Loop:** - **Stroke Volume (SV)**: The width of the loop indicates the stroke volume (difference between end-diastolic volume and end-systolic volume). - **Cardiac Output (CO)**: The area within the loop represents the work done by the heart and is related to cardiac output. - **Contractility**: A shift of the loop upwards indicates increased contractility (higher pressures for the same volume), while a downward shift indicates decreased contractility. - "a" represents diastolic filling of the left ventricle (preload). - "b" represents the beginning of systole; tension of the left ventricle increases during isovolumic contraction. - When left intraventricular pressure exceeds afterload, the aortic valve opens and blood is ejected out of the left ventricle - "c" on the loop. Left ventricular volume rapidly diminishes during this phase; pressure initially spikes, then lowers as blood is ejected. - The event labeled "d" represents isovolumic relaxation. When afterload exceeds end-systolic left ventricular pressure, the aortic valve closes, and diastole begins - In **aortic stenosis** the pressure volume loop will be **taller and narrower** - The pathophysiology associated with aortic stenosis is that blood within the left ventricle cannot be ejected quickly (the stenotic valve may be critically narrowed). - Afterload as experienced by the left ventricle is greatly increased. These effects cause marked reductions in ejection fraction and stroke volume. - The pressure-volume loop will be taller along the y-axis because left ventricle needs to overcome the greater "afterload" it experiences from outflow obstruction. - The pressure-volume loop will be narrower due to the reduced ejection fraction/stroke volume; elevated left ventricular end-systolic volume, elevated left ventricular end-diastolic volume - In **mitral stenosis** the pressure volume loop will have a smaller loop with a leftward shift **[Sliding Filament Theory]** A diagram of a cross-bridge formation Description automatically generated **[Frank Starling Law of the Heart *(FORMATIVE)*:\ ]** The curve reflects the heart\'s intrinsic ability to vary the strength of contraction based on the volume of blood it is filled with (EDV/preload).  Compares the contraction strength, stroke volume and end diastolic volume. The strength of contraction and the volume of blood ejected by the ventricles is dependent on the blood volume present in the ventricles at the end of diastole.  - The ventricles are made of cardiac muscle cells. The muscle cells contain bundles of myofibrils (long chains of sarcomeres). The sarcomere is the smallest structure in the muscle capable of contraction. - Low EDV, sarcomeres are squeezed together with few myosin heads bound to actin, weak contraction, low SV. - Increased EDV, sarcomeres stretch with more myosin-actin binding, greater strength of contraction and SV increases. - When the EDV becomes too high, myosin and actin are too far apart and myosin and actin binding decreases and results in a weaker contraction and lower SV. - Moving from left to right, the Frank-Starling curve goes "uphill", peaks, then goes "downhill". One reason for the shape of the curve along its left side is that as left ventricular end diastolic pressure (preload) increases, contractility increases. This directly proportional relationship is not maintained indefinitely along all pressures. Eventually, the ability of the heart to maintain optimal contractility with ever-increasing left ventricular end-diastolic volumes is lost (with too much stretch, myocardial filaments within the sarcomeres lose their overlap and are unable to contract). This rationale is the reason for the "downhill" slope of the curve in the right-sided portions. - Positive inotropes and exercise will move the curve upwards and left and increase contraction and stroke volume. For equivalent left ventricular end-diastolic pressures - Negative inotropes and heart failure will move the curve downward and right and decrease the strength of contraction and stroke volume. The "diseased heart" curve reveals that, for equivalent LVEDPs, there is diminished myocardial contractility in comparison with resting states. This is likely the result of damage to the myocardium and its contractility. This heart is likely to demonstrate an inability to optimally increase the ejection fraction and stroke volume with increased preload. [https://www.osmosis.org/learn/Pressure-volume\_loops] **[Congestive Heart Failure :]** the heart cannot pump or fill properly to supply enough blood to meet the body's demands. It leads to fluid accumulation in the lungs or tissues. - **Systolic Heart Failure:** contractility and ejection issue. - **Diastolic heart Failure:** contractility sufficient, problem with filling- relaxation failure - Can either be left sided, right sided, or biventricular. - Can be acute, chronic, acute exacerbation of chronic HF. - One will lead to the other, but terms refer to which one was first. - Most extreme occurs when all compensatory mechanisms have failed and result in **cardiogenic shock**. **[Pathophysiology]** **Acute Systolic HF** Myocardial dysfunction → activation of SNS and RAAS → vasoconstriction, increased HR, increased SVR, fluid retention → volume overload leads to pulmonary edema and hypoxemia → increased cardiac workload → systemic effects due to decreased perfusion (MODS)  **Chronic Systolic HF** Myocardial dysfunction → activation of SNS and RAAS → vasoconstriction, increased HR, increased SVR, fluid retention → **ventricular remodeling from hormones** (hypertrophy, chamber dilation, apoptosis) → worsened ventricular performance → systemic effects due to decreased perfusion (MODS) → exercise intolerance, physical inactivity, deconditioning  **Diastolic HF** Stiff LV → impaired LV filling → pulmonary edema ***[FORMATIVE]*** - All heart failure describes the inability of the heart as a pump to provide sufficient cardiac output. - Systolic failure is evident when the heart cannot eject its preload optimally ("pump failure"). Sometimes, this is because the myocardium loses contractility; other times, this is because afterload is too great. - Diastolic failure results from a heart that cannot fill properly. Many times, this is because the ventricle is stiff and cannot stretch. Preload is reduced in this case. - One similarity of systolic and diastolic heart failure is that, in extreme cases, patients will be hypotensive. - One difference between systolic and diastolic heart failure is found in management. Although systolic failure may cause hypotension, it is often experienced in the setting of hypertension; treatment requires afterload reduction (vasodilators, diuretics, etc.). In diastolic heart failure, therapies aimed at increasing preload and left ventricular filling (e.g. fluid administration, beta-adrenergic receptor antagonists, etc.) are important. +-------------+-------------+-------------+-------------+-------------+ | Feature | Systolic HF | Diastolic | Left HF | Right HF | | | | HF | | | +=============+=============+=============+=============+=============+ | Definition | Impaired | Impaired | Dysfunction | Dysfunction | | | contraction | filling of | of the left | of the | | | of the | the heart- | ventricle | right | | | heart | reduced | affecting | ventricle | | | | preload | systemic | affecting | | | | (preserved | circulation | pulmonary | | | | ejection |. | circulation | | | | fraction) | |. | +-------------+-------------+-------------+-------------+-------------+ | EF | Reduced EF, | **Preserved | May have | Typically | | | usually \< | ** | reduced | not | | | 40% | usually \> | ejection | assessed in | | | | 50% b/c | fraction | the same | | | | there is a | (systolic) | way, often | | | | low total | or | related to | | | | volume | preserved | volume | | | | | (diastolic) | overload. | | | | (Normal EF |. | | | | | (50%-70%)) | | | +-------------+-------------+-------------+-------------+-------------+ | Parameters | Low CO, low | Low CO, low | |   | | | SV, high | SV, high | | | | | EDP, high | EDP, | | | | | EDV, | **normal | | | | | dilated LV | EDV**, | | | | | | normal LV | | | +-------------+-------------+-------------+-------------+-------------+ | Causes | **Ischemia* | **Ventricul | **Ischemic | **Left-side | | | * | ar | heart | d | | | (due to MI, | hypertrophy | disease, | heart | | | CAD), | ** | hypertensio | failure, | | | **Dilated | (due to | n, | left to | | | cardiomyopa | hypertensio | valvular | right | | | thy** | n, | disease, | cardiac | | | (weak | AS, | cardiomyopa | shunt, cor | | | ventricle), | valvular | thy, | pulmonale** | | | arrhythmias | disease), | hypertrophy | can be | | | , | hypertrophi | , | caused by | | | valvular | c | arrhythmias | chronic | | | dysfunction | or | ** | lung | | | | | | disease | | | | restrictive |   | (hypoxia | | | | cardiomyopa | | leads to | | | | thy |   | pulmonary | | | | | | artery | | | |   | | vasoconstri | | | | | | ction, | | | |   | | right | | | | | | ventricular | | | |   | | hypertrophy | | | | | | and | | | | | | failure), | | | | | | **PE, RV | | | | | | infarct** | | | | | | | | | | | |   | +-------------+-------------+-------------+-------------+-------------+ | Signs/Sympt | BP normal | BP is | **Backed up | **Backed up | | oms | or low, | usually | to the | to the | | | fatigue, | high, | lungs.** | body.** | | | shortness | fatigue, | | | | | of breath, | shortness | Pulmonary | Peripheral | | | fluid | of breath, | edema, | edema, | | | retention, | pulmonary | dyspnea, | ascites, | | | S3. | edema, S4. | orthopnea, | jugular | | | | | paroxysmal | venous | | | | | nocturnal | distension, | | | | | dyspnea, | hepatosplen | | | | | fatigue, S3 | omegaly, | | | | | or S4. | cardiac | | | | | | cirrhosis. | | | | |   | | | | | | |   | +-------------+-------------+-------------+-------------+-------------+ | | Beta-blocke | Beta | Similar to | Diuretics, | | | rs, | blockers, | systolic | treatment | | | ACE/ARB, | ACE/ARB, | heart | of | | | diuretics, | diuretics | failure. | underlying | | | dilators, | (low dose), | | causes, | | | inotropes, | aldosterone | | managing | | | aldosterone | antagonists | | fluid | | | antagonists | , | | balance. | | | | **Ca | | | | | | channel | | | | | | blockers** | | | +-------------+-------------+-------------+-------------+-------------+ | Contraindic | Negative | Positive |   |   | | ated | inotropes | inotropes | | | | | (ex: Ca | | | | | | channel | | | | | | blockers), | | | | | | Beta | | | | | | blockers in | | | | | | acute phase | | | | | | worsens | | | | | | contraction | | | | +-------------+-------------+-------------+-------------+-------------+ https://www.osmosis.org/learn/Heart\_failure:\_Pathology\_review **[Concentric and Eccentric Hypertrophy *(FORMATIVE)*:]** - Concentric hypertrophy symmetrically affects all parts of the chamber and the left ventricle mass-to-cavity ratio appears to be greater than 2:1. The volume of blood that the ventricle is able to accommodate is diminished. Preload is therefore decreased (the enlarged ventricle is unable to fill with blood). Diminished ventricular filling that leads to diminished stroke volume (even if ejection fraction is preserved) leads to decreased cardiac output; this is an example of diastolic heart failure. - The EKG of a patient with left ventricular hypertrophy would have greater amplitude because there is more muscle mass, esp in V4, V5, and V6 **[Cardiomyopathies *(FORMATIVE):*]** - Cardiomyopathies can be ischemic or non-ischemic - Non-ischemia: tachy-induced cardiomyopathy (from afib), stress induced cardiomyopathy/Takotsubo, secondary to metabolic syndromes, HCOM, amyloidosis (infiltrative due to abnormal buildup of proteins that makes it restrictive) **[Cardiac Dysrhythmias: ]** **Abnormal automaticity:** an area of the heart fires off action potentials at a rate that is faster than the SA node. **Heart beat is driven by ventricles, rather than SA node.** **Abnormal reentry:** results from scar tissues because it doesn't conduct electricity. The electrical signal goes around the scar and each cycle causes the ventricles to contract. Accessory (extra) pathway between the atria and the ventricles, like the **Bundle of Kent in Wolff- Parkinson White Syndrome.** The signal moves back up the accessory pathway to create ad reentry circuit that causes extra contractions that occur in-between the signals coming from the SA node. **SA Node Dysrhythmias:** **Sinus Bradycardia:** the spontaneous depolarizing events through the SA node are happening more slowly over time. - HR less than 60 beats per min - Normally occurs in young, healthy individuals and athletes. - Pathologically occurs in increased vagal tone, hypoxia, hypothermia, medications (Ca+ channel blockers or beta blockers) - Treatment: (only if symptomatic) Atropine (blocks PNS) **Sinus Tachycardia:** the spontaneous depolarizing is occurring too quickly through the SA node. - HR greater than 100 beats per min - Normally occurs with physiological stress - Treatment: underlying cause **Atrial Dysrhythmias:** originate outside of SA node - Abnormal P waves - Atrial tachycardias \> 100 beats per min - **Focal Atrial Tachycardia:** begins at one point in atria - **Multifocal Atrial Tachycardia:** begins at many points in atria - **Atrial Flutters:** originate at atria due to **reentry mechanisms** - Between 250 to 350 bpm of atria - The rate limiting factor is the AV node because it will slow down the a-flutter and only some beats will be conducted (about 170 bpm) - Saw tooth P-waves - Causes: structural abnormalities, toxic drug effect - Treatment: Beta blockers, Ca+ channel blockers - Not life threating, but increase risk of clots - **Atrial Fibrillation:** originate at atria due to **reentry mechanisms** - \> 350 bpm of atria - Due to multifocal atrial tachycardia - The rate limiting factor is the AV node because it will slow down and only some beats will be conducted (about 170 bpm). - Treatment: beta blockers, Ca+ channel blockers, cardioversion - Not life threating, but increase risk of clots **SVTs** are arrhythmias originating above the ventricles, usually in the atria or AV node, and are characterized by a rapid heart rate. - **Atrioventricular Reentrant Tachycardia (AVRT**): involves a **reentrant circuit** within the AV node, causing rapid conduction of electrical impulses between the atria and ventricles. **Need functioning AV node conduction and accessory pathway to create reentrant circuit.** - exists between atria and ventricles - Signal can go forward or in anterograde direction, depends on the refractory period - The AV node will slow down the signal, however the accessory pathway will not. - Ex: Wolff Parkinson White (WPW) - Shortened PR interval, and slow slope of QRS complex (delta wave) - If the reentrant circuit is in a refractory period, the signal will travel to the ventricles through the AV node and then back up through the reentrant circuit to then stimulate the AV node. This will lead to tachycardiac and a reentrant circle. - **Atrioventricular Nodal Reentrant Tachycardia (AVNRT):** abnormal loop of electricity, or abnormal reentrant circuit **directly involves the AV node** and the tissue around it (NO ACCESSORY PATHWAY). - There are two pathways that travel through the AV node- a slow pathway with shorter refractory period and a fast pathway with longer refractory period - Can become problematic due to refractory periods and premature beats that may create an reentrant circuit in the AV node - **Antodromic** the impulse is traveling up the AV node after going down an accessory pathway and is more severe because it causes a widen QRS. **Orthodromic** travels down the AV node and comes back up an accessory pathway and causes a narrow QRS. **AV Node Dysrhythmias:** - **AV Node Block (Heart Block):** at the AV node there is a *delay* or absence of atrial depolarization propagating to the ventricles. - **First Degree Heart Block**: delay in atrial depolarization (P wave) at AV node to depolarize the ventricles. - \> 0.2 sec - Prolonged PR interval - No treatment - **Second Degree Heart Block:** delay in atrial depolarization at AV node to depolarize the ventricles. Some beats from the atria are not conducted through the AV node into the ventricles at all. - **Mobitz 1** - PR interval gets longer and longer and there is a dropped beat - Longer, longer, longer, drop, now you have a Wenckebach - No treatment - **Mobitz 2** - P waves with non-conducted beats (no QRS) - Treatment: pacemaker - **Third Degree Heart Block:** the atrial depolarization events are not related at all to the QRS complexes. The ventricles depolarize and contract independently of the atria. - SA node and AV node spontaneously depolarize, independent of each other. - 30-55 bpm - P waves are not related to QRS complexes. **Ventricular Dysrhythmias:** originate in ventricular myocardium or His-Purkinje system - **Ventricular Tachycardia** - Ventricular contraction \> 100 bpm (up to 250 bpm) - Defined as more than 3 PVC's in a row - Decreased CO - **Focal Ventricular Tachycardia:** ventricular pacemaker cells become irritated and begin firing at faster rates than the SA node. May be due to medications, ischemia, electrolyte imbalances, illicit drugs. - **Reentrant Ventricular Tachycardia:** Scar tissue in the ventricular myocytes lead to creation of a split pathway that goes around scar tissue. This can be effected by fast and slow conduction speed and long and short refractory periods - **Monomorphic VT** originates from the same place in the ventricles (reentrant or focal) - **Polymorphic VT** originates from different places in the ventricles. (focal in multiple areas - Treatment: Cardioversion (Drugs, electrical), Defibrillation, Ablation, ICD - **Ventricular Fibrillation:** Quivering of ventricular muscle fibers from uncoordinated muscle contraction - Stress, damage, and scar tissue to the cardiac muscle tissue causes it to be structurally and electrically changed. Different muscle cells will conduct signals faster or slower and can lead to **reentrant circuits,** each firing at different times - Multifocal points that are depolarizing - Decreased CO - Treatment: Defibrillation to allow SA node to reset, ICD A black screen with white text Description automatically generated [**https://www.youtube.com/watch?v=tRuvXP-H164**](https://www.youtube.com/watch?v=tRuvXP-H164) [**https://www.youtube.com/watch?v=2GnjgTRybq8**](https://www.youtube.com/watch?v=2GnjgTRybq8) [**https://www.osmosis.org/learn/Ventricular\_tachycardia?from=/md/foundational-sciences/pathology/cardiovascular-system/dysrhythmias/supraventricular-tachycardia**](https://www.osmosis.org/learn/Ventricular_tachycardia?from=/md/foundational-sciences/pathology/cardiovascular-system/dysrhythmias/supraventricular-tachycardia) [**https://www.osmosis.org/learn/Ventricular\_fibrillation?from=/md/foundational-sciences/pathology/cardiovascular-system/dysrhythmias/supraventricular-tachycardia**](https://www.osmosis.org/learn/Ventricular_fibrillation?from=/md/foundational-sciences/pathology/cardiovascular-system/dysrhythmias/supraventricular-tachycardia) **https://www.youtube.com/watch?v=3nbwBAzJEGE**Bottom of Form **[Neurology]** **Central Nervous System** - Consists of brain and spinal cord - Afferent: sensory - Efferent: motor - **Telencephalon:** includes the cerebral hemispheres (cortical areas of white and grey matter) and basal ganglia (deep into the cortex, they are grey masses). - **Diencephalon:** hypothalamus (controls pituitary), thalamus (sensory relay- every sensory system goes through here) - **Brainstem:** midbrain, pons, medulla (vegetative functions- breathing, cardiac) - **Frontal lobe:** personality, intelligence, abstract thinking, language (Broca's area), primary motor cortex (precentral gyrus) - **Parietal lobe:** primary sensory cortex (postcentral gyrus), sensory - **Temporal lobe:** auditory, language (Wernicke's area) - **Occipital Lobe:** vision - **Cerebellum:** is divided into the vermis and the cerebellar hemispheres. It is anchored to the brainstem by 3 cerebellar peduncles. It is responsible for balance and coordination. - The central sulcus separates the frontal and parietal lobes. - The corpus callosum is the band of fibers that connects the right and left brain **[Stroke]** - sudden focal neurological deficit due to part of the brain losing its blood supply - **Focal Neurological deficit:** corresponds to the region of the brain that is affected - **Anterior Cerebral Artery (ACA) Stroke:** effects feet and legs - **Middle Cerebral Artery (MCA) Stroke:** effects the hands, arms, face, language centers of dominant hemisphere - **Posterior Cerebral Artery (PCA) Stroke:** effects the visual cortex - Motor pathways are damaged leading to immediate flaccid paralysis and later spastic paralysis and hyperreflexia. - Sensory pathways are damaged leading to numbness, reduces pain and vibration sensation. - Motor and sensory effects occur on the side that is **contralateral** from the stroke - In brain stem strokes, both sides are affected - Assessed using NIHSS and CT scan - Blood appears white on CT scan, indicating hemorrhagic stroke. Absence of blood in an ischemic stroke appears black because there is no perfusion. - Symptoms often include dysphagia and increased ICP. - Need formal speech and swallow - Headache, vomiting, papilledema - **Cushing's triad:** hypertension (widened pulse pressure), bradycardia, irregular respirations - Elevated ICP can be treated with brief hyperventilation to cause cerebral vasoconstriction, HOB \> 30, Mannitol - CPP is the net pressure that drives blood flow to the brain, ensuring brain tissues receives oxygen and nutrients. CPP= MAP -- ICP - ICP is the pressure within the skull exerted by the brain tissue, CSF, and blood volume. Normal is 7-15 mmhg. **[Ischemic Stroke]** 3 types, majority of strokes - Treatment: Thrombolysis with recombinant tissue plasminogen activator **(rTPA)** to dissolve blood clots throughout the body. - It is time sensitive and should be given within 4.5 hours from last known well (3 hours in DM and elderly). - It focuses on the cells in the **penumbra** (the area of brain tissue surrounding the core of the damage) - Can cause bleeding or convert stroke to hemorrhagic, therefore there are contraindications - **Mechanical thrombectomy** in internal carotids, ACA, or MCA within 24 hours of symptom onset - **Thrombectomy with stent retriever** can be done for ICA or proximal segments of the MCA if within 6 hours. - **Rectal aspirin** if unable to perform other options - Loss of autoregulation occurs, but cerebral autoregulation kicks in since parts of the brain are not being perfused. - Allow to permissive hypertension to prevent hypoperfusion, but not too high to prevent reperfusion hemorrhage after TPA (below 180/105 if given TPA, 220/120 with no TPA) - Labetalol or nicardipine are drugs of choice 1\. **Thrombotic Stroke:** caused by a blood clot that develops in the blood vessels inside the brain. - Atherosclerosis, fibromuscular dysplasia - local arterial obstruction due to inflammatory and non-inflammatory diseases that effects small and large vessels - **Lacunar strokes**: small vessel occlusion usually due to hypertension, smoking or diabetes. - s/sx: hemiparesis, ataxia, dysarthria, numbness in the contralateral face, arm and leg 2\. **Embolic Stroke:** caused by a blood clot or plaque debris that develops elsewhere in the body and then travels to one of the blood vessels in the brain through the bloodstream. - **Cardioembolic**: arises from the heart (often in afib) - **Thromboembolic/Atheroembolic**: embolus dislodges from a thrombus in an artery - **Paradoxical Embolus**: dislodges from thrombus in veins (DVT) and goes through PFO or atrial defect into the LA and then brain 3\. **Hypoxic Stroke:** systemic hypoperfusion - Infants due to ischemia during birth, septic shock, drowning **Patho:** Decreased blood flow→ lack of O2, glucose in brain→ decrease ATP production, electrochemical gradient→ cell death  - Two Mechanisms of Cell Death  - Sodium Buildup: water follows sodium→ cell swelling, death - Calcium Buildup: creates oxygen radicals→ damages mitochondrial, lysosomal lipid membrane→ seeping of degradative enzymes, apoptosis-inducing factors→ cell death  - Two Zones: - **Ischemic Core:** brain tissue dies from ischemia within few minutes of stroke  - **Ischemic Penumbra:** periphery of affected region preserved due to collateral circulation; chance of survival if blood restored quickly  A table with text on it Description automatically generated **[Hemorrhagic Stroke:]** hematoma from broken blood vessels damages and compresses brain tissue. - **Intracerebral hemorrhage (ICH):** bleeding occurs in **brain**, usually due to hypertension. - Blood vessel trauma, rupture→ creates pool of blood→ tissue, surrounding blood vessel compression→ hypoxia in downstream tissue → damage due to compression and lack of O2 - **Subarachnoid hemorrhage (SAH):** bleeding occurs in the **subarachnoid space** between pia mater and arachnoid mater of meninges, usually due to ruptures aneurysms or AV malformations. - Presents with the worst headache, N/V, stiff neck, photophobia - Vasospasm: Blood clot lysis→ release if spasmogenic substances (ex: endothelin), decreased production of nitric oxide→ vasospasm due to smooth muscle contraction→ brain ischemia  - Given Nimodipine (Calcium channel blocker) to prevent vasospasm in blood vessels that are irritated by the hemorrhage - Hydrocephalus - **Subdural Hemorrhage (SDH):** rare, but spontaneous subdural hematomas can occur in the context of aneurysm rupture, coagulopathies, and thrombocytopenia. - **Anticoagulants and anti-thrombolytics are contraindicated** - Treatment: surgical coil of clip to block off the broken blood vessel, craniotomy to relieve the pressure - Maintain BP below 140 to prevent further bleeding - Labetalol or nicardipine is drug of choice **[Transient Ischemic Attack (TIA)]** - Short lasting neurological dysfunction due to transient focal ischemia, **without infarction.** Stroke symptoms resolve within minutes to hours. - *No ischemia/visible infarcts on CT/MRI* - Blood vessel occlusion/stenosis→ decreased blood flow in affected region→ neurological dysfunction  - ABCD2 score evaluates the risk of subsequent stroke after having a TIA - Age, blood pressure, clinical features, duration, diabetes - Low score of 1-2 do not require hospitalization - Moderate score (4-5) and high score (6-7) should be hospitalized immediately - No acute treatment- watch and wait due to high risk for stroke A diagram of a brain and a diagram of the brain Description automatically generated  **[Circle of Willis Vascular Supply]** The circle of Willis gives rise to numerous vessels which supply the cerebrum and cerebellum via the **internal carotid arteries** (ICA) and the **vertebral arteries** (VA). This can broadly be divided into the anterior circulation and posterior circulation: - Anterior circulation (internal carotid system): - Anterior cerebral arteries - Anterior communicating artery - Middle cerebral arteries - Posterior circulation (vertebrobasilar system): - Posterior cerebral arteries - Posterior communicating arteries - The ICA's supply the ACA and MCA. - The VA's join to form the Basilar artery and supply the PCA. - The Circle of Willis is located in the subarachnoid space (space between arachnoid mater and pia mater). - **Middle cerebral artery (MCA)**: Supplies the lateral aspects of the cerebral cortex, including the temporal lobe and infero-lateral surface of frontal and parietal lobes. It also supplies deeper parts of the brain through the lenticulostriate to the corpus striatum (caudate and lenticular nucleus). This is the most common site for strokes. - **Anterior cerebral artery (ACA)**: Supplies the anteromedial surface of the cerebral cortex, including the antero-lateral and medial aspects of the frontal and parietal lobes. - **Posterior cerebral artery (PCA)**: Supplies the posterior and inferior surfaces of the cerebral cortex, including the occipital lobe, parts of the temporal lobe, and the visual cortex. - **Basilar artery/vertebral arteries**: Supply the brainstem and cerebellum. - **Posterior communicating arteries:** originate from the PCA's and connect to the ACA's to close the Circle of Willis. - **Anterior communicating arteries:** connect the right and left ACA.  - The **motor homunculus** (located in the **precentral gyrus** of the frontal lobe, or primary motor cortex) and the **sensory homunculus** (located in the **postcentral gyrus** of the parietal lobe, or primary somatosensory cortex) represent a **map** of the body. Each part of the homunculus corresponds to a specific region of the body and density of neurons that are dedicated to that region, with **contralateral** control/representation (meaning the left side of the brain controls the right side of the body, and vice versa). It is represented as a body lying on top of the brain, where each part of the body represents its corresponding brain area.  - **Motor homunculus**: Regions near the medial part of the precentral gyrus control the lower limbs (legs and feet), while more lateral regions control the upper limbs (arms, hands), face, and speech muscles (on the lateral part of the gyrus). - **Sensory homunculus**: The same general somatotopic layout applies to sensory input, with different areas corresponding to different body parts. - The medial motor and sensory homunculus, representing the lower body, are supplied by the ACA.  - The lateral homunculus representing the upper body and face is supplied by the MCA.  #### [Middle Cerebral Artery (MCA) Stroke] - **Contralateral** hemiparesis and hemianesthesia (loss of sensation) primarily affecting the **face** and **upper limb**. - The MCA arises from the internal carotid artery and supplies the **lateral** aspects of the frontal, parietal, and temporal lobes, including the motor and sensory cortices responsible for the face, upper limbs, and speech. It is the most common site for ischemic strokes. - **Other MCA Stroke Signs**: - **Aphasia** (if in the dominant hemisphere, typically the left hemisphere): Damage to Broca\'s or Wernicke\'s area. - **Broca's Aphasia (Non-fluent Aphasia)** - **Anatomical Location**: Broca\'s area, located in the left inferior frontal gyrus (posterior part of the frontal lobe) - **Vascular Supply**: Left MCA -- superior division of the MCA - **Clinical Features**: Patients exhibit non-fluent speech, with preserved comprehension. Speech is effortful and consists mainly of content words, with limited grammatical structures - **Wernicke's Aphasia (Fluent Aphasia)** - **Anatomical Location**: Wernicke\'s area, located in the left superior temporal gyrus (posterior part of the superior temporal gyrus) - **Vascular Supply**: Left MCA -- inferior division of the MCA - **Clinical Features**: Patients produce fluent speech, but it is often nonsensical or includes neologisms. Comprehension is significantly impaired - **Conduction Aphasia:** - **Anatomical Location**: Arcuate fasciculus, which connects Broca\'s and Wernicke\'s areas, and the supramarginal gyrus - **Vascular Supply**: Typically, the left MCA but can vary depending on the extent of the lesion - **Clinical Features**: Patients have fluent speech and relatively good comprehension but struggle with repetition and often make phonemic errors - **Global Aphasia:** - **Anatomical Location**: Extensive damage to both Broca\'s and Wernicke\'s areas, as well as surrounding areas in the left hemisphere. Often involves the entire perisylvian region - **Vascular Supply**: Large infarct in left MCA or its branches, affecting a large area - **Clinical Features**: Severe impairment in both expression and comprehension. Patients may only produce a few words and understand very little. - **Hemineglect** (if in the nondominant hemisphere, typically the right hemisphere): Loss of awareness of one side of the body or space. #### [Anterior Cerebral Artery (ACA) Stroke] - **Contralateral** weakness (hemiparesis) and sensory loss more pronounced in the **lower limb** and **trunk**. - The ACA supplies the **medial** aspects of the frontal and parietal lobes, including the motor and sensory cortices for the **lower limbs**. This is why ACA strokes often present with **leg weakness** and **sensory loss**. - **Other ACA Stroke Signs**: - **Urinary incontinence** (due to involvement of frontal lobe areas responsible for bladder control). - **Akinetic mutism** (if the stroke is large, affecting the prefrontal cortex). #### [Posterior Cerebral Artery (PCA) Stroke] - PCA strokes typically cause **visual deficits**, such as **homonymous hemianopia** (loss of vision in one half of the visual field in both eyes). - Motor and sensory deficits are generally **not prominent**, but can occur if the stroke affects the **thalamus** or parts of the **parietal** lobe. - The PCA arises from the basilar artery and supplies the occipital and temporal lobes, including the **visual cortex**. It also supplies parts of the thalamus, which may contribute to sensory deficits if involved. - If the thalamus is involved signs and symptoms include sensory loss, impaired memory, and altered LOC. #### [Basilar/Vetibral Arteries] - Strokes in the vertebrobasilar system (including the vertebral and basilar arteries) can affect brainstem, cerebellum, and occipital lobes. - Supplies: The posterior circulation, including the brainstem, cerebellum, and parts of the occipital lobes and temporal lobes. - Symptoms: These strokes can cause symptoms like dizziness, vertigo, ataxia, double vision, dysarthria, dysphagia, or even locked-in syndrome (if the brainstem is involved) ***FORMATIVE*** - A patient that presents with right sided weakness and a right facial droop is likely to have a stroke in the left MCA. Based on the homunculus and the primary motor cortex, there is contralateral upper limb and facial involvement. - Most patients with an MCA occlusion have aphasia because the language centers of the brain, like Broca's and Wernicke's area are fed by the MCA vessel. - As most people are right-handed, they are left-hemisphere dominant. Dominance -- in neurology -- refers to the hemisphere which has the control over language, speech, analytic processing, and mathematical/higher order operations. The role of the dominant hemisphere differs from that for the non-dominant hemisphere, which is the location for artistic and abstract thought and visual-spatial relationships. As stated before, a right-handed person is generally left-hemisphere dominant. A left-handed person has a greater chance of being right-hemisphere dominant. If the patient above were right-hemisphere dominant, it is possible that, in the context of a cerebral infarction in the distribution of the left middle cerebral artery, no aphasia would be noted because Wernicke's and Broca's areas would be in the contralateral cerebral cortex.   **Watershed Infarct and Ischemia Penumbra (*FORMATIVE)*:** - Watershed infarcts occur when there is a global blood loss and reduction in blood flow (hypotension, shock, cardiac arrest) to the brain at the junctions (or \"watersheds\") between two major arteries that supply the brain. These areas are particularly vulnerable to ischemia because they are located at the border regions between different vascular territories, where blood flow is relatively lower and more sensitive to changes in perfusion pressure. There are two main watershed zones. - **ACA-MCA watershed zone**: Located between the **ACA** and the **MCA** territories. This zone is vulnerable to ischemia when perfusion is reduced in either of these arteries. - **MCA-PCA watershed zone**: Located between the **MCA** and the **PCA** territories. - In the context of cerebrovascular disease, the **ischemic penumbra** refers to the vulnerable area of brain tissue surrounding the initial area of infarction (primary brain injury site) that, with early and aggressive treatment, is salvageable.   - A **watershed infarct** describes an infarct within the vulnerable zone of tissue distal to and in between the distribution of two or more cerebral arteries.  - A similarity between the penumbra and the watershed area is that both zones represent vulnerable areas of the brain's "real estate", susceptible to irreversible infarction when there is a prolonged interruption of blood flow as provided by their corresponding vascular distributions.   - The difference between the ischemic penumbra and the watershed area is evident when describing how these areas infarct. The ischemic penumbra is usually surrounding an initial, primary area of infarction caused by thrombosis or embolism of a single arterial vessel. Infarction of the penumbra occurs with persistent lack of blood flow to this area of distribution. With prompt treatment, the penumbra may be saved. A watershed infarct, in contrast, occurs when there is global hypoperfusion to the brain (as in septic shock, severe cardiogenic shock, or other situations \[e.g. surgery\] where blood pressure is dangerously low). In periods of global hypoperfusion, the watershed area -- being located between two or more arteries -- infarcts because it does not receive its own direct blood supply. It is much less likely to be saved in these circumstances.   **CPP and ICP:** ### Cerebral Perfusion Pressure (CPP) - CPP is the net pressure that drives blood flow to the brain, ensuring that brain tissues receive oxygen and nutrients. - CPP=MAP−ICP - Adequate CPP is essential for maintaining cerebral blood flow. Low CPP can lead to brain ischemia, while excessively high CPP can cause brain swelling and further elevate ICP. ### Intracranial Pressure (ICP) - ICP refers to the pressure within the skull exerted by brain tissue, CSF, and blood volume. - Normal ICP ranges from 7 to 15 mmHg in adults. Pressures above 20 mmHg are considered elevated and dangerous over time. - High ICP can compress brain structures, decrease CPP, and reduce blood flow to the brain, which can result in brain tissue damage. **Coagulation Cascade** Blood vessels are lined with an endothelial layer surrounded by connective tissue in the basement membrane (contains collagen). Hemostasis is achieved through primary hemostasis (1 & 2) and secondary hemostasis (3): 1 ) Vascular spasm or **vasoconstriction** to mitigate blood loss - Damage to the blood vessel causes the release of **thromboxane A2, serotonin, norepinephrine, and endothelin** which will cause the smooth muscle to contract 2\) **Platelet plug** - Endothelial cells and platelets release **Von Willebrand Factor** when damaged. - Platelets adhere to VWF that is bound to exposed collagen. Collagen and platelets are negatively charged so they are held together by VWF. - Genetic conditions with high or low VWF will affect clotting - They start to form a platelet plug 3\) **Coagulation (cascade)** - Clotting factors are I- XIII, however Factor 3, 4, and 6 do not exist. They are proteins that are produced in the liver. They have to be proteolytically activated to function. Ultimately leads to the activation of Fibrin to create a fibrin mesh that surrounds and reinforced the platelet plug - If there is liver damage, there will be an issue with production of the proteins - The clotting cascade has an intrinsic and extrinsic pathway the converges on a common pathway - Intrinsic pathway is due to damage to the blood vessel. There will be damage to the endothelia, collagen available and platelets available. - Factor XII comes into contact with damaged endothelia, collagen and aggregated platelets and becomes Factor XIIa - Factor XIIa actives Factor XI - Factor XIa activates Factor IX - Factor IXa activates Factor X - Factor IXa needs Vitamin K, Calcium, and Factor VIII to active Factor X. - Factor XII exposed to damaged blood vessel Factor XIIa Factor XIa Factor IXa Factor Xa - Extrinsic pathway is due to damage to the tissue, but the blood vessel itself is not damaged. There is a release of tissue factors like thromboplastin. - Factor VII comes into contact with thromboplastin it becomes VIIa - Factor VIIa activates Factor X - Factor VIIa needs Vitamin K, Calcium, tissue factor - Common pathway - Activated Factor Xa needs three things: Vitamin K, Calcium and Factor V - Factor Xa converts **Prothrombin (Factor II)** into **Thrombin** - Thrombin activated **Fibrinogen (Factor I)** into **Fibrin** - **Fibrin forms the clot.** Fibers are embedded into the platelets, but it needs to be cross linked by **Factor XIII.** - The purpose of Vitamin K and Calcium: - They effect factors 2, 7, 9 and 10. - 2 + 7 = 9 NOT 10 - Vitamin K carboxylates the factors, which makes them more negative so Calcium can bind to them and the bind to collagen and platelets The liver is responsible for producing several clotting factors that are essential for proper hemostasis. These clotting factors are part of the coagulation cascade, which involves a series of enzymatic reactions leading to the formation of a clot. The liver synthesizes most of these factors, as well as proteins that regulate clotting (like antithrombin, protein C, and protein S). ### **[Liver Functions Involved in Coagulation:]** 1. **Synthesis of Coagulation Factors**: The liver produces the majority of clotting factors (I, II, V, VII, IX, X, XI, and XII). Deficiencies in these factors, due to liver dysfunction, can lead to prolonged clotting times and increased bleeding risk. 2. **Synthesis of Anticoagulants**: - **Protein C and Protein S**: Both are vitamin K-dependent proteins that regulate the clotting cascade by inactivating Factors Va and VIIIa, helping to prevent excessive clotting. - **Antithrombin**: A protein that inhibits thrombin and other clotting factors (especially Factor Xa and thrombin). 3. **Vitamin K Metabolism**: - The liver also plays a crucial role in the metabolism of **vitamin K**, which is required for the synthesis of several clotting factors (Factors II, VII, IX, and X). Vitamin K deficiency, whether due to liver disease or inadequate intake, can impair clotting. ### **[Coagulation Tests and Liver Disease]** #### Prothrombin Time (PT): - **PT** measures the time it takes for blood to clot, specifically testing the extrinsic and common coagulation pathways (Factors I, II, V, VII, and X). - **Prolonged PT**: A prolonged PT suggests a deficiency in one or more of the clotting factors produced by the liver. In liver disease, PT is often prolonged due to reduced synthesis of clotting factors, especially Factor VII (which has a short half-life). - **International Normalized Ratio (INR)**: PT is often reported as the INR, which standardizes PT values to account for variations in test performance between different laboratories. An elevated INR (greater than 1.5) is a sign of poor liver function and increased bleeding risk. **Normal PT**: 11-13.5 seconds\ **Normal INR**: 0.8-1.2 #### Activated Partial Thromboplastin Time (aPTT): - **aPTT** measures the time it takes for blood to clot via the intrinsic and common pathways, primarily evaluating the function of Factors I, II, V, VIII, IX, X, XI, and XII. - **Prolonged aPTT**: Can indicate a deficiency in these clotting factors, which can be seen in liver disease or with the use of anticoagulants like heparin. However, aPTT is generally less sensitive to liver dysfunction than PT, as many of the intrinsic pathway factors (like Factor VIII) are produced outside the liver (e.g., by endothelial cells). **Normal aPTT**: 25-35 seconds #### Fibrinogen: - **Fibrinogen (Factor I)** is produced by the liver and is essential for blood clot formation. Low fibrinogen levels can be a sign of liver disease, particularly in conditions like acute liver failure or DIC**.** - **Decreased fibrinogen levels**: Seen in severe liver disease, acute liver failure, or conditions like DIC or severe infection. **Normal Fibrinogen**: 200-400 mg/dL #### Platelet Count: - The liver produces thrombopoietin, a hormone that stimulates platelet production in the bone marrow. In chronic liver disease, platelet production can be impaired, and splenomegaly can cause increased platelet sequestration, leading to thrombocytopenia - Low platelet count**:** A hallmark of cirrhosis or portal hypertension**.** **Normal Platelet Count**: 150,000-450,000 platelets per microliter #### 5. Vitamin K Levels: - Vitamin K is essential for the synthesis of certain clotting factors (II, VII, IX, and X). In liver disease, vitamin K deficiency can contribute to prolonged PT/INR. - Vitamin K deficiency can be due to malabsorption (in cirrhosis or obstructive jaundice) or impaired conversion in the liver. **Normal Vitamin K levels**: This is measured by vitamin K-dependent coagulation factor levels or specific vitamin K assays. **[GI System:]** The function of the GI tract is motility, digestion, absorption, storage and elimination, water and electrolyte balance and immune function (GALT- gut associated lymphoid tissue). - These events are mediated by many neural and endocrine control mechanisms. - Involves enteric and parasympathetic nervous system - Ach is the neurotransmitter of the vagus, which innervates the entire GI tract, and promotes all aspects of digestion - Peristalsis and mixing movements of the GI tract are possible due to two layers of smooth muscle, an outer longitudinal layer and an inner circular layer - Non-propulsive movements are segmental contractions associated with mixing - Propulsive movements are peristalsis contractions to move food forward **ORAL CAVITY** - Mechanical digestion: mastication via teeth breaks down food to increases the surface area to allow enzymatic activity - Chemical digestion: - **Saliva:** - Produces water and mucin → lubricate food, oral mucosa, ease propulsion of food from oral cavity to esophagus - Antibacterial properties - **Salivary amylase:** initiates breakdown of carbohydrates - **Lingual lipase:** minimal breakdown of lipids **ESOPHAGUS** - Muscular transport tube extending from pharynx to stomach - Aids in the transport of food to the stomach to undergo digestion - **Primary peristalsis** is initiated by swallowing - **Secondary peristalsis** is elicited by distension of the esophagus. - Hormonal cascade that occurs if food is stuck in the throat and causes chest pain similar to that of a heart attack - **Upper esophageal sphincter (UES):** controls opening of pharynx to allow food to enter esophagus - Made of skeletal muscle, voluntary control - **Lower esophageal sphincter (LES):** controls opening to stomach - Made of smooth muscle, involuntary control - Relaxation of the LES is mediated by both the vagus nerve and by intrinsic properties of smooth muscle, including important inhibitory effects by VIP and NO. - Defective sphincter (weakened or doesn't close properly) → **GERD: reflux of acidic stomach contents into the esophagus or the abnormal exposure of esophageal mucosa to gastric acid →** over time continuous reflux, can develop *esophagitis* (damage to the esophageal mucosa that leads to dysphagia) **→** or *Barrett's esophagus* → esophageal cells are destroyed and replaced with gastric mucosa cells → if they undergo dysplasia → can lead to esophageal adenocarcinoma - Can be caused from a hiatal hernia (weak LES due to protruding stomach through diaphragm), obesity (excessive weight increases pressure on stomach), pregnancy (progesterone/relaxin relax smooth muscles including the LES, also increased pressure), smoking (nicotine relaxes LES by NO release, reduced saliva (buffer) production because it damages mucosal tissues), iatrogenic causes such as medications that relax the LES, dietary causes, gastroparesis, genetic causes **STOMACH *(FORMATIVE)*** - **Cephalic phase**: cephalic stimulation (neural stimulation) from the smell, sight, taste, or thought of food sends signals via the PNS vagus nerve to enteric nervous system (submucosal plexus) - Function: increase volume of gastric juice to prepare for entry of food - Enteric systemic: Ach stimulates → - **Mucus cells:** secrete mucus to increase volume of stomach lining to prepare for acid production - **Ghrelin:** Often referred to as the \"hunger hormone,\" it stimulates appetite and promotes food intake. - **Enterochromaffin-like (ECL)** cells are stimulated by the enteric nervous system and gastrin. They secrete histamine which stimulates parietal cells - **G cells:** secrete gastrin into bloodstream - **Gastrin:** hormone that stimulates the secretion of gastric acid and promotes motility - **Gastric phase**: food entering the stomach stimulates CNS via stretch receptors and increased pH (food entering acidic environment) → PNS vagus nerve signals enteric nervous system (submucosal plexus & myenteric plexus) - Mixing waves: to break down food into chyme - **Parietal cells:** secrete HCl to increase gastric acid production. Also secrete gastroferrin and intrinsic factor. - Intrinsic factor: a glycoprotein necessary for the absorption of B12 in the small intestine. - **Chief cells:** secrete pepsinogen (converted to pepsin in presence of HCl to break down proteins) - **G cells:** secrete gastrin - Gastrin is stimulating parietal cells to release acid (also stimulates chief cells) - Lipase: an enzyme responsible for the initial digestion of triglycerides - H. Pylori - Colonizes the antrum of the stomach - Uses a cluster of flagella for motility which is essential for the colonization of gastric mucosa. - Can cause duodenal ulcers or gastric ulcers, but it is more likely to cause a **duodenal ulcer- test question** **[Peptic Ulcer Disease]** - Gastric ulcer, greater pain- usually worse after eating - Duodenal ulcer, decreased pain - Disruptions between the balance of protective factors and aggressive factors - Protective factors: - mucus bicarbonate barrier- thick layer of mucus that protects the stomach wall and buffers acidity - prostaglandins- stimulate secretion of mucus and bicarb and enhance blood flow to the stomach lining - epithelial cell integrity and rapid renewal- constant turnover of cells relining the stomach - mucosal blood flow - growth factors and cytokines - Aggressive factors: - gastric acid (HCl) - pepsin - H. Pylori - NSAIDs- can lead to **gastric ulcer** inhibition of COX-1 enzyme reduced prostaglandin production decreased mucus and bicarb secretion reduced blood flow to gastric mucousa leading to direct irritation of the gastric lining by NSAIDs, stomach acid and pepsin damage to epithelial cells and inflammation leading to ischemia and gastric ulcer - bile salts - smoking - ETOH - stress- increases acid production and decreases blood flow to the stomach because it activates the SNS **SMALL INTESTINE** - Divided into three parts. - **Duodenum**: the first segment, C-shaped, and retroperitoneal - Function: receives chyme from the stomach and secretions from the pancreas and gallbladder. It is the primary site of chemical digestion  - **Jejunum:** The middle portion, intraperitoneal, and has a thicker wall with larger diameter  - Function: major site for nutrient absorption  - It contains villi and microvilli to increase surface area and for the brush border, containing enzymes that will finalize nutrient digestion. - **Ileum:** the final and longest part, ends at the ileocecal valve where it joins with the large intestine  - Function: absorbs vitamin B12, bile salts, and remaining nutrients - The main site for digestion and absorption. - **Intestinal phase:** chyme entry into the duodenum for further digestion and absorption - Stimulated by duodenal stretch receptors and decreased pH (acidic chyme) which stimulates CNS → PNS vagus nerve → enteric nervous system (myenteric plexus) inhibited= inhibit gastric acid secretion, gastric motility - Increased acidity → stimulates **secretin** - Increase bile production - Increase release of *bicarbonate-rich fluid* from pancreas to neutralize acid - Acid needs to be neutralized because all SI enzyme function at neutral pH - Decrease gastric acid secretion and motility - Lipids & proteins in duodenum → **stimulate CCK** - Stimulate *gallbladder contraction* - Stimulate pancreatic *enzyme release* - Relax sphincter of Oddi - **Decrease gastric acid production** and motility - Pancreatic amylase digests carbohydrates - Trypsin and peptidases digest proteins - Pancreatic lipase digests lipids - When the breakdown of complex molecules is complete, absorption of carbohydrates and proteins occurs through the brush border on the microvilli of the small intestine. - **GIP (Gastric Inhibitory Peptide):** Inhibits gastric motility/secretion and stimulates insulin release in response to the presence of nutrients in the SI. - **Motilin:** Stimulates motility in the stomach and SI and plays a role in moving contents toward the large intestine **[Ulcerative Colitis v.s. Crohn's Disease]** - UC: genetic predisposition and environmental component abnormal immune response to intestinal microbiota chronic mucosal inflammation in the colon, starting in the rectum and extending proximally **WITHOUT** skip lesions T helper cells release cytokines that **amplify inflammation** results in **superficial ulcerations** and mucosal damage leads to hemorrhage increased permeability, chronic diarrhea, rectal bleeding, and anemia - Can lead to toxic megacolon, increases colorectal cancer risk - Crohn's: genetic mutation of (**NOD 2** or ATG 16L1) abnormal immune response to intestinal microbiota chronic inflammation **of total thickness** of the intestinal wall (transmural inflammation) - Can lead to deep ulcerations, fissures, granulomas - Cytokine release inflammation fibrosis Fistulas, strictures, abscess - Malabsorption nutritional deficiency A table with a list of medical information Description automatically generated **LARGE INTESTINE** - Water reabsorption - Electrolyte reabsorption - Vitamin reabsorption= A, D, E, K - Storage of fecal matter - diarrhea= increased water loss, large intestine is not reabsorbing enough - constipation= decreased water in stool, large intestine is reabsorbing too much water **LIVER** - Bile production, storage (glycogen), detoxification, nutrient interconversion, synthesis (albumin, clotting factors), phagocytosis (Kupffer cells)  - Bile is produced by hepatocytes, excreted into bile ducts **[Liver Lobule *(FORMATIVE)*]** - Functional unit of the liver made up of hepatocytes - Lobule is hexagonal in cross-section with a central vein at its center and portal veins at its 6 corners - Hepatic artery & hepatic portal vein are arterioles that converge at the sinusoid into the central vein (venule) - Hepatic artery (stems from cephalic trunk of abdominal aorta)= 25% oxygen-rich, nutrient poor blood - Hepatic portal vein (stems from superior/inferior mesenteric arteries)= 75% oxygen-poor, nutrient rich blood - - Hepatic vein= venule that carries deoxygenated blood out of liver and to the heart - Hepatic vein→IVC→SVC→RA - Hepatocytes and Kupffer cells (specialized liver macrophages) pick up nutrients, toxins, and other substances and metabolize them. - Removes the bacteria before the blood flows into the vena cava - Waste products generated from hepatocellular metabolism are drained from the liver lobule by the bile canaliculi and towards the bile ducts. **Portal Triad (*FORMATIVE)*** - Each portal triad contains a branch of the portal vein, a branch of the hepatic artery, and a bile duct - The physiological functional unit of the liver is the hepatic acinus - Divided into three zones that correspond to distance from arterial oxygen supply (portal triad)  - **ZONE 1:** located proximate to and between opposing portal triads. It is highest in oxygen and nutrient gradients. - has the greatest metabolic activity and is commonly affected by infections (ex: HBV, HCV) - **ZONE 2:** surrounds Zone 1 - **ZONE 3-** surrounds Zone 2 and is proximate to the hepatic vein in the centrilobular area. Lowest in oxygen and nutrient gradients - **most susceptible to ischemic injury especially in the setting of cardiac arrest because it receives blood flow last- centrilobular necrosis\*** - Highest concentration of CYP-450 enzymes - Commonly affected by toxins and drugs requiring metabolism and detoxification **Hepatic Metabolism** - The integration of phase 1 and phase 2 reactions ensures the efficient detoxification and elimination of potentially harmful xenobiotics from the body. - **First pass metabolism:** oral meds are subject to undergoing metabolism before entering the systemic circulation to exert PD effect - Meds are entering the stomach → absorbed through gut wall → enter hepatic portal vein → liver metabolism - Decreased bioavailability, need to give higher doses to compensate for this - Bypass this with sublingual, IV meds - **Cytochrome P450:** responsible for Phase I of metabolism ( Oxidation, reduction, hydroxylation, hydrolysis) - Converts lipid soluble products into more polar substances which undergo Phase II reactions with conjugation to increase water solubility → increase excretion - Primarily catalyzed by enzymes such as UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and glutathione S-transferases (GSTs) - Conjugation, sulfation, glucuronidation, methylation - Ex: unconjugated bilirubin (lipid soluble) enters hepatic portal vein → undergo Phase I and Phase II reactions → conjugated bilirubin (water soluble) = excretion in urine **Liver Cirrhosis** tissue becomes scarred and fibrotic due to virus, alcohol, etc. - Stellate cells are stimulated by damaged hepatocytes in the liver and produce collagen to form scar tissue. The scar tissue compresses the sinusoid and leads to **portal hypertension**. - increased portal vein resistance due to structural narrowing of vessel and contraction of portal venules leading to back up of blood flow. - Starling forces: there is an increase in hydrostatic pressure from venous stasis and decreased of capillary osmotic pressure due to decreased albumin that causes ascites. - Fluid is easily moved into tissues into open spaces such as the peritoneal cavity, leading to **ascites** and can lead to congestive splenomegaly. - **Portosystemic shunt:** shunts blood away from liver due to high pressures and into systemic circulation. - Causes renal vasoconstriction, decreased GFR and **hepatorenal failure** - Leads to decreased functional liver portal triads and thus decreased liver function - Less detoxification leads to hepatic encephalopathy. - Ammonia is normally produced in the GI tract and metabolized in the liver, but in liver failure builds up in the brain and can lead to asterixis and coma. - Increased unconjugated bilirubin and leads to jaundice - Decreased albumin - Decreased clotting factors leads to coagulation issues - Varices are enlarged submucousal veins in the esophagus or stomach - Develop due to portal hypertension from liver cirrhosis. This leads to a back-up of blood to the stomach and esophagus leading to varices - If severe they can burst and lead to esophageal bleeding and hematemesis https://www.youtube.com/watch?v=7cdDCZobDpw **BILIARY TREE** - Bile is produced by hepatocytes and stored in the gallbladder - **Bile canaliculi** (portal triad) converge to form **bile ducts →** converge to form common hepatic duct into gallbladder - Cystic duct from gallbladder & pancreatic duct join common hepatic duct to form **COMMON BILE DUCT** before it empties into the duodenum - **Sphincter of Oddi:** controls the flow of bile released from common hepatic duct (between gallbladder and small intestine - Contraction of sphincter of oddi increases biliary pressure - **FUNCTIONS OF BILE:** - Fat emulsification agent → breaks down fat into fat globules to increase surface area to allow enzymatic activity - Alkalinization of the duodenum - Excretory pathway for bilirubin and products of metabolism - **Cholecystokinin (CCK):** produced in the duodenum - Stimulated by fat and protein - Stimulates gallbladder contraction → increasing flow of bile into the duodenum **Hepatic Injuries: Cholestatic and Hepatocellular Injury** ### Cholestatic Liver Injury Cholestasis refers to a reduction or stoppage in bile flow, which can occur at the level of the liver (intrahepatic) or the