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Guyton & Hall Textbook of Medical Physiology - Chapter 14

Overview of the Circulation: Pressure, Flow, and Resistance

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Purpose of the Circulation

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1. Physical Characteristics of the Circulation

• Systemic circulation (also called peripheral circulation) - supplies all body tissues except the lungs. Contains ~84% of total blood volume.
• Pulmonary circulation - serves the lungs for gas exchange. Contains ~9% of total blood volume.
• The heart itself holds ~7% of blood volume.

Fig. 14.1 - Blood Distribution

Functional Parts

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2. Blood Pressures Across the Circulation

Fig. 14.2 - Pressure Profile

• Left ventricle: 0-120 mm Hg (systole/diastole)
• Aorta: ~80-120 mm Hg (diastolic/systolic)
• Arterioles: drops steeply to ~25-35 mm Hg (where greatest resistance exists)
• Capillaries: ~17 mm Hg at arterial end, ~8 mm Hg at venous end
• Right atrium / venae cavae: ~0 mm Hg
• Pulmonary artery: ~15-28 mm Hg (about 1/6th of systemic arterial pressure)

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3. Basic Principles: The Interplay of Pressure, Flow, and Resistance

Ohm's Law Applied to the Circulation

F = ΔP / R

• F = blood flow (mL/sec or L/min)
• ΔP = pressure difference between two ends of a vessel (P₁ - P₂, in mm Hg)
• R = vascular resistance

• Flow is directly proportional to the pressure difference, NOT the absolute pressure.
• If pressure at both ends of a vessel is equal (e.g., both 100 mm Hg), flow is zero despite high pressure.
• The formula rearranges to: ΔP = F × R and R = ΔP / F

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4. Blood Flow

• Definition: quantity of blood passing a point per unit time (mL/min or L/min)
• Normal cardiac output at rest: ~5,000-6,000 mL/min (5-6 L/min) in a 70-kg adult
• Total blood flow = cardiac output (the amount ejected into the aorta each minute)
• Men typically have 10-20% higher cardiac output than women at rest, mainly due to larger body mass

Measuring Blood Flow

• Applied outside a blood vessel
• A magnetic field is placed around the vessel; blood moving through it generates an electrical voltage proportional to flow rate
• Can record changes in under 1/100th of a second - captures pulsatile flow accurately

• Transmits ultrasonic waves into flowing blood
• Moving red blood cells reflect these waves with a Doppler frequency shift proportional to flow velocity
• Can be used non-invasively; also detects direction of flow

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5. Blood Pressure Measurement

• Standard unit: millimeters of mercury (mm Hg) - standardized since Poiseuille's manometer in 1846
• Pressure = force exerted by blood per unit area of vessel wall
• 1 mm Hg = 1.36 cm H₂O (mercury is 13.6× denser than water)

• Mercury manometers can only follow slow pressure changes (up to ~1 cycle/2-3 sec)
• Electronic transducers use a thin metal membrane that deflects with pressure changes, recorded via:
  • Capacitance transducer (membrane capacitance changes with deflection)
  • Inductance transducer (iron slug moves into a coil)
  • Resistance wire transducer (stretched wire changes resistance)
• These can accurately record pressure cycles up to 500 cycles/sec

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6. Resistance to Blood Flow

Units of Resistance

• 1 peripheral resistance unit (PRU) = pressure difference of 1 mm Hg producing flow of 1 mL/sec
• Total peripheral resistance (TPR) of the entire systemic circulation is normally ~1 PRU

Poiseuille's Law - Determinants of Resistance

R = 8ηL / πr⁴

• η (eta) = viscosity of blood
• L = length of the vessel
• r = radius of the vessel

Conductance (inverse of resistance)

Conductance = 1/Resistance = Flow/Pressure difference

Vessels in Series vs. Parallel

• Total resistance = sum of individual resistances
• R_total = R₁ + R₂ + R₃ ...
• The segment with the highest resistance (arterioles) determines most of the total resistance

• Total conductance = sum of individual conductances
• C_total = C₁ + C₂ + C₃ ...
• Adding more parallel vessels reduces total resistance
• Removing a limb or kidney removes a parallel pathway, increasing total peripheral resistance
• Blood flow through each organ is determined by its own individual resistance and the pressure gradient

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7. Effect of Hematocrit and Blood Viscosity

Hematocrit

• Definition: percentage of blood volume occupied by red blood cells
• Normal values: ~42% in men, ~38% in women
• Measured by centrifuging blood in a calibrated tube
• Anemia: decreased hematocrit → decreased viscosity → reduced resistance → increased flow tendency
• Polycythemia: increased hematocrit → markedly increased viscosity → dramatically increased resistance

• At hematocrit 0-40%: modest viscosity increase
• Above 60%: viscosity rises steeply - cardiac workload becomes dangerously high

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8. Vascular Distensibility and Compliance

Distensibility

Vascular distensibility = Increase in volume / (Increase in pressure × Original volume)

• Veins are ~8× more distensible than arteries of similar size
• Arteries are relatively stiff - they act as a "pressure reservoir" (Windkessel effect), smoothing out the pulsatile cardiac output into a more continuous flow
• Pulmonary arteries are ~6× more distensible than systemic arteries (since they operate at much lower pressures)

Compliance (Capacitance)

Vascular compliance = Increase in volume / Increase in pressure

• Compliance = distensibility × volume
• Systemic vein compliance = ~24× that of a systemic artery (8× more distensible AND 3× larger volume)
• Systemic arterial system: at 700 mL blood → pressure ~100 mm Hg; at 400 mL → pressure ~0 mm Hg
• Systemic venous system: requires hundreds of mL change to alter venous pressure by just 3-5 mm Hg - this is why transfusing 500 mL into a healthy person doesn't dramatically change circulatory function

Effect of Sympathetic Stimulation on Volume-Pressure Relationships

• Sympathetic stimulation → increases vascular smooth muscle tone → higher pressure at same volume (vessels "stiffen")
• Sympathetic inhibition → lower pressure at same volume (vessels "relax")
• This gives the nervous system powerful control over blood distribution, especially venous return to the heart

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Summary Table: Key Concepts of Chapter 14

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• Guyton and Hall Textbook of Medical Physiology, Chapter 14 (ISBN 9780443111013)

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GUYTON & HALL - TEXTBOOK OF MEDICAL PHYSIOLOGY

CHAPTER 9: Cardiac Muscle; The Heart as a Pump and Function of the Heart Valves

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OVERVIEW

• Right heart - pumps blood through the pulmonary circulation (lungs)
• Left heart - pumps blood through the systemic circulation (all other organs and tissues)

• Atrium - weak primer pump; helps move blood into the ventricle
• Ventricle - main pumping chamber; supplies force to propel blood into the circulation

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SECTION 1: CARDIAC MUSCLE PHYSIOLOGY

Three Types of Cardiac Muscle

• Specialized fibers contract feebly (few contractile fibrils) but serve as the excitatory and conductive system.

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SECTION 2: CARDIAC MUSCLE ANATOMY

Histology

• Cardiac muscle fibers arranged in a latticework - fibers divide, recombine, and spread again.
• Striated - same as skeletal muscle
• Contains typical myofibrils with actin and myosin filaments, lying side by side; filaments slide during contraction (same cross-bridge mechanism as skeletal muscle)

Left Ventricular Torsion (Twisting Motion)

• The LV has complex fiber layers running in different directions, enabling a wringing/twisting motion during systole.
• Subepicardial (outer) layer - spirals leftward
• Subendocardial (inner) layer - spirals rightward (opposite direction)
• Midwall fibers run circumferentially
• Arrangement forms a double helix
• During contraction:
  • Subepicardial fibers rotate LV apex counterclockwise (viewed apex-to-base)
  • Base rotates clockwise
  • Net result: wringing motion pulling base toward apex during systole
• At end systole: LV acts like a loaded spring - recoils/untwists during diastole, allowing rapid ventricular filling

Intercalated Discs

• Dark bands crossing cardiac muscle fibers visible on histology
• Actually cell membranes separating individual cardiac muscle cells
• Cardiac muscle = many individual cells connected at intercalated discs
• At intercalated discs, cell membranes fuse into gap junctions (communicating junctions)
  • Gap junctions allow free diffusion of ions between cells
  • Ions carry electrical current → cardiac muscle is an electrical syncytium

Functional Syncytium

• The heart has two separate syncytia:
  1. Atrial syncytium - forms the walls of the two atria
  2. Ventricular syncytium - forms the walls of the two ventricles
• Atria and ventricles are separated by fibrous tissue except at the AV bundle (bundle of His)
• When an action potential is initiated anywhere in the atrial syncytium → spreads to ALL atrial fibers
• When an action potential is initiated in the ventricular syncytium → spreads to ALL ventricular fibers
• This is the basis of all-or-nothing contraction of cardiac muscle

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SECTION 3: ACTION POTENTIALS IN CARDIAC MUSCLE

Resting Membrane Potential

• About -85 mV in ventricular muscle (slightly less negative than in skeletal muscle, which is -90 mV)

Phases of the Ventricular Action Potential

• Fast Na⁺ channels open → rapid influx of Na⁺
• Membrane potential rises from -85 mV toward +20 mV
• Fast channels are "activation gates" - open within milliseconds when membrane potential rises above threshold (~-65 mV)
• These channels have two gates: activation gate (opens rapidly) and inactivation gate (closes within milliseconds)

• Fast Na⁺ channels inactivate
• Brief K⁺ efflux

• Duration: ~0.2 seconds (atrial) to ~0.3 seconds (ventricular)
• Caused by: L-type (slow) calcium channels open → sustained Ca²⁺ influx
• Also: decreased K⁺ permeability (K⁺ channels close at onset of plateau)
• Without the plateau: contraction would be too brief for adequate pumping

• L-type Ca²⁺ channels close
• K⁺ channels reopen → rapid K⁺ efflux → membrane repolarizes back to resting potential

Comparison: Cardiac vs. Skeletal Muscle Action Potential

Why Cardiac Muscle Cannot Tetanize

• The action potential duration is nearly as long as the contraction itself
• During the plateau, the muscle is in its absolute refractory period - it cannot be re-excited
• This prevents tetanic (sustained) contractions that would stop the heart's pumping action

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SECTION 4: EXCITATION-CONTRACTION COUPLING IN CARDIAC MUSCLE

T-Tubule System

• Cardiac T tubules are 5 times the diameter of skeletal muscle T tubules (25× the volume)
• Inside T tubules: large quantities of mucopolysaccharides that are electronegatively charged and bind abundant stored calcium ions
• T tubule openings pass directly through the cardiac muscle cell membrane into extracellular spaces
• Therefore: calcium in T tubules = from extracellular fluid surrounding cardiac cells

Calcium-Induced Calcium Release (CICR)

1. L-type Ca²⁺ channels on T tubule membrane open → Ca²⁺ flows from T tubule into sarcoplasm
2. This Ca²⁺ triggers ryanodine receptor (RyR) Ca²⁺ release channels on the sarcoplasmic reticulum (SR) → massive release of Ca²⁺ from SR (calcium-induced calcium release)
3. Total sarcoplasmic [Ca²⁺] rises → Ca²⁺ binds troponin C → conformational change → tropomyosin moves → actin-myosin cross-bridge cycling → contraction

Key Difference from Skeletal Muscle

• Skeletal muscle: almost entirely SR-derived Ca²⁺ (extracellular Ca²⁺ barely matters)
• Cardiac muscle: both SR and extracellular Ca²⁺ are important
  • A heart placed in calcium-free solution quickly stops beating
  • Therefore, extracellular Ca²⁺ concentration directly affects force of cardiac contraction

Relaxation

1. Ca²⁺ influx suddenly cut off as action potential ends
2. SERCA2 (sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase) pumps Ca²⁺ back into SR
3. Na⁺/Ca²⁺ exchanger extrudes Ca²⁺ out of cell (Na⁺ enters)
4. Na⁺/K⁺-ATPase then pumps Na⁺ back out
5. Sarcoplasmic Ca²⁺ falls below threshold → troponin-tropomyosin complex returns to blocking position → relaxation

Duration of Contraction

• Contraction begins a few milliseconds after the action potential begins
• Continues until a few milliseconds after the action potential ends
• Duration of contraction ~ duration of action potential (including plateau)
• Atrial muscle: ~0.2 seconds
• Ventricular muscle: ~0.3 seconds

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SECTION 5: THE CARDIAC CYCLE

Phases of the Cardiac Cycle

DIASTOLE (Relaxation/Filling Phase)

• Ventricles relaxed; AV valves open; semilunar valves closed
• Blood flows passively from great veins/pulmonary veins → atria → ventricles
• ~70-80% of ventricular filling occurs passively before atrial contraction

ATRIAL SYSTOLE ("Atrial Kick")

• P wave on ECG → atrial depolarization → atrial contraction
• Atrial contraction adds 20-30% of additional ventricular filling (the "booster pump")
• Right atrial pressure rises 4-6 mm Hg; Left atrial pressure rises 7-8 mm Hg
• Important in exercise or tachycardia when diastolic filling time is short

VENTRICULAR SYSTOLE

• QRS complex on ECG → ventricular depolarization → ventricles start to contract
• Ventricular pressure rises rapidly
• AV valves close as soon as ventricular pressure exceeds atrial pressure (produces S1)
• Semilunar valves still closed (aortic pressure ~80 mm Hg)
• Volume does not change (both sets of valves closed) - "isovolumetric"
• Duration: ~0.05 seconds

• Ventricular pressure exceeds aortic/pulmonary artery pressure → semilunar valves open
• LV pressure rises to ~120 mm Hg (systolic); RV to ~25 mm Hg
• Blood rapidly ejected into aorta and pulmonary artery
• About 70% of total stroke volume ejected in this phase

• Ventricular pressure begins to fall
• Ejection continues but slows
• Remaining ~30% of stroke volume ejected

VENTRICULAR DIASTOLE (Beginning)

• T wave on ECG → ventricular repolarization → ventricles begin to relax
• Ventricular pressure falls rapidly
• Semilunar valves close when ventricular pressure drops below aortic pressure (produces S2)
• AV valves still closed
• Volume unchanged again - "isovolumetric"
• Duration: ~0.04 seconds

• Ventricular pressure drops below atrial pressure → AV valves open
• Blood rushes rapidly from atria into ventricles
• ~70-80% of total ventricular filling occurs here

• Filling continues slowly
• Blood entering veins and atria slowly passes into ventricles

Atrial Pressure Waves: a, c, and v Waves

• Right atrial: a wave = 4-6 mm Hg; Left atrial: a wave = 7-8 mm Hg

Ventricular Pressures and Volumes

• End-diastolic volume (EDV): ~110-120 mL
• End-systolic volume (ESV): ~40-50 mL
• Stroke volume (SV) = EDV - ESV = ~70 mL
• Ejection fraction (EF) = SV/EDV = 70/120 = ~60%
• Systolic pressure: ~120 mm Hg
• Diastolic pressure: ~0 to 8 mm Hg

• Same volumes as LV
• Systolic pressure: ~25 mm Hg
• Diastolic pressure: ~0 to 8 mm Hg

Effect of Increased Heart Rate on the Cardiac Cycle

• Increased HR → shorter cycle duration
• Systole shortens but NOT proportionally as much as diastole
• At normal HR of 72 bpm → systole = ~40% of cycle
• At 3× normal HR → systole = ~65% of cycle
• Very fast heart rates: diastole inadequate → incomplete ventricular filling → reduced stroke volume

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SECTION 6: FUNCTION OF THE HEART VALVES

Atrioventricular (AV) Valves

• Mitral valve (left AV): two leaflets; guards left AV orifice
• Tricuspid valve (right AV): three leaflets; guards right AV orifice
• Both are prevented from bulging too far back into atria (prolapsing) by chordae tendineae - fibrous strings attached to valve leaflets and to papillary muscles on the ventricular walls
• Papillary muscles contract along with the ventricle → pull chordae tendineae → keep valves closed tight without reversing into atria
• If papillary muscles fail (e.g., MI) → valve prolapse → regurgitation

Semilunar Valves

• Aortic valve and pulmonary valve
• Each has three semilunar (half-moon) shaped cusps
• Open when ventricular pressure exceeds arterial pressure
• Close when arterial pressure exceeds ventricular pressure at end systole
• No chordae tendineae - close by mechanical pressure alone
• Designed to prevent blood backflow from aorta/pulmonary artery into ventricles

Why Valves Open and Close Silently vs. With Sound

• Valve opening = slow process → no noise normally
• AV valve closure (S1): slower, lower-pitched, longer sound
• Semilunar valve closure (S2): rapid snap, higher-pitched, shorter sound
• Both sounds caused by vibration of valve leaflets and surrounding blood/tissue

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SECTION 7: WORK OUTPUT OF THE HEART

• Energy used to move blood from low-pressure veins to high-pressure arteries
• Work = stroke volume × mean arterial pressure

• Energy used to accelerate blood to ejection velocity
• Proportional to mass of blood × (velocity of ejection)²
• Normally only ~1% of total work output
• Exception: aortic stenosis → blood ejected at very high velocity through narrowed valve → kinetic energy work can exceed 50% of total work output

• RV external work = ~1/6 of LV external work (due to ~6-fold lower pulmonary vs. systemic pressure)

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SECTION 8: VENTRICULAR VOLUME-PRESSURE RELATIONSHIPS

Volume-Pressure Diagram (Fig. 9.10 in Guyton)

• Up to ~150 mL: diastolic pressure increases little → blood can fill easily
• Above ~150 mL: diastolic pressure rises rapidly (fibrous pericardium stretched to limit; cardiac connective tissue fully stretched)

• Even at low volumes, systolic pressure increases significantly when ventricle contracts
• Maximum systolic pressure at ~150-170 mL
• At very high volumes: systolic pressure actually decreases because actin and myosin filaments are pulled beyond optimal overlap (like in skeletal muscle length-tension relationship)

The Cardiac Loop (Fig. 9.11)

1. Diastolic filling (right side, low pressure): volume increases from ESV to EDV
2. Isovolumetric contraction: pressure rises, volume constant
3. Ejection: pressure maintained at high level, volume decreases (SV ejected)
4. Isovolumetric relaxation: pressure falls, volume constant

• Total area inside the loop = net external work output of the ventricle per beat

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SECTION 9: REGULATION OF HEART PUMPING

9A. Intrinsic Regulation - The Frank-Starling Mechanism

• Frank-Starling Law: Within physiological limits, the greater the volume of blood filling the ventricle (increased end-diastolic volume = increased preload), the greater the force of contraction and stroke volume
• Mechanism: More filling → cardiac muscle fibers stretched → optimal actin-myosin overlap → stronger cross-bridge formation → greater force
• Also: increased stretch increases sensitivity of troponin to Ca²⁺
• Practical significance: If extra blood flows into the heart from peripheral veins, the heart automatically pumps it all out - output = input
• This prevents venous backup and maintains balanced output between right and left hearts

• Plot: stroke work vs. left ventricular end-diastolic pressure (LVEDP)
• Normal resting LV: diastolic pressure ~2 mm Hg; LVEDP ~0-6 mm Hg when exercising
• As LVEDP (preload) increases, stroke work increases
• At very high filling pressures: curve plateaus or may decline (overstretched)

9B. Extrinsic Regulation - Autonomic Nervous System

• Norepinephrine released from sympathetic nerve endings → binds β₁-adrenergic receptors
• Chronotropic effect: increases heart rate from ~70 bpm up to 180-200 bpm (rarely 250 bpm)
• Inotropic effect: may double force of contraction
• Increases Ca²⁺ entry and release, and speeds up SERCA activity (faster relaxation too)
• Overall: sympathetic stimulation can increase maximum cardiac output 2-3 fold
• Normal baseline: sympathetic nerves discharge continuously at low rate → heart pumps ~30% above baseline (no sympathetic)
• Sympathetic inhibition → HR and contractility fall → cardiac output may drop ~30% below normal

• At any given right atrial pressure (filling pressure):
  • Increased sympathetic stimulation → shifts curve upward and to the left (more output)
  • Increased parasympathetic stimulation → shifts curve downward and to the right (less output)

• Acetylcholine released from vagus nerve → binds M₂ muscarinic receptors
• Vagal fibers distributed mainly to atria (SA node, AV node), not much to ventricles
• Strong vagal stimulation can stop the heart for a few seconds
• Heart eventually "escapes" and beats at 20-40 bpm (junctional or ventricular escape rhythm)
• Decreases strength of atrial (not much ventricular) contraction by 20-30%
• Combined effect of rate reduction + slight contractility decrease → ventricular pumping reduced by 50% or more

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SECTION 10: EFFECT OF IONS ON HEART FUNCTION

Potassium (K⁺)

• Reduces resting membrane potential (less negative)
• Reduced membrane potential → decreased action potential amplitude and strength
• Heart becomes dilated and flaccid
• Heart rate slows
• Very high K⁺ (>8-10 mEq/L) can cause the heart to stop in diastole (cardiac arrest)

• Membrane hyperpolarizes (more negative resting potential)
• Arrhythmias (spontaneous extra beats)

Calcium (Ca²⁺)

• More Ca²⁺ available to enter during plateau → stronger contraction
• Very high Ca²⁺ → heart stops in systole (spastic contraction) - called "calcium rigor"

• Decreased contraction strength
• Very low Ca²⁺ → cardiac muscle relaxes, heart stops in diastole

• In skeletal muscle: SR stores alone are sufficient for full contraction
• In cardiac muscle: T tubule extracellular Ca²⁺ is indispensable (SR stores alone insufficient)

Temperature Effects

• Increased temperature → increases heart rate, slightly increases force of contraction
• Decreased temperature (hypothermia) → slows heart rate significantly; during cardiac surgery, heart can be stopped by cooling

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SECTION 11: SPECIAL FEATURES OF CARDIAC MUSCLE METABOLISM

• Cardiac muscle is an obligate aerobe - it cannot sustain itself on anaerobic metabolism for more than a few minutes
• Primary fuel: Free fatty acids (60-70% of energy at rest)
• Also uses: glucose, lactate, amino acids, ketone bodies
• During exercise or increased workload: glucose utilization increases
• Cardiac muscle has very high mitochondrial density (25-35% of cell volume) - reflects its continuous high energy demands
• Creatine phosphate (phosphocreatine) serves as a rapid energy buffer during sudden increases in demand
• Myocardial O₂ consumption = best index of overall cardiac energy expenditure
• Ischemia (insufficient O₂ supply) → rapid switch to anaerobic glycolysis → lactate production → acidosis → impaired contraction

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SECTION 12: CARDIAC RESERVE AND OVERALL PUMPING CAPABILITY

• Heart normally operates at only 20-25% of its maximal capacity at rest
• Cardiac reserve: the extra output the heart can achieve above resting level
• Normal cardiac reserve = 300-400% of resting cardiac output
• Even if atria fail to function as "primer pumps," most people will not notice at rest (the ventricles still receive ~70-80% passive filling)
• Symptoms of atrial failure become apparent only during exercise (when filling time is short and atrial kick becomes critical)

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KEY NUMBERS TO REMEMBER - CHAPTER 9

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GUYTON & HALL - TEXTBOOK OF MEDICAL PHYSIOLOGY

CHAPTER 10: Rhythmical Excitation of the Heart

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OVERVIEW

1. Generates electrical impulses to initiate rhythmical contraction
2. Conducts those impulses rapidly and in the correct sequence through the heart

• Atria contract ~1/6 second (about 0.16 sec) ahead of ventricular contraction → allows ventricular filling before ejection
• All portions of the ventricles contract almost simultaneously → generates maximum pressure in the ventricular chambers
• This system is susceptible to damage by ischemia (reduced coronary blood flow) → bizarre rhythms, abnormal contraction sequences, severe reduction in pumping → can cause death

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SECTION 1: THE SPECIALIZED EXCITATORY AND CONDUCTIVE SYSTEM

Components (from top to bottom)

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SECTION 2: THE SINUS (SINOATRIAL) NODE

Anatomy

• Small, flattened ellipsoid strip of specialized cardiac muscle
• Size: ~3 mm wide × 15 mm long × 1 mm thick
• Location: superior posterolateral wall of the right atrium, immediately below and slightly lateral to the opening of the superior vena cava
• Fiber diameter: 3-5 μm (much smaller than surrounding atrial muscle fibers at 10-15 μm)
• Fibers have almost no contractile myofilaments
• Sinus nodal fibers connect directly with atrial muscle fibers → any action potential in sinus node spreads immediately into the atrial wall

Self-Excitation of Sinus Fibers (Automaticity)

Resting Membrane Potential in SA Node vs. Ventricular Muscle

• SA cell membranes are naturally leaky to Na⁺ and Ca²⁺
• Constant inward leak of positive ions → partially depolarizes the resting membrane → resting potential only reaches -55 to -60 mV instead of -90 mV

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SECTION 3: MECHANISM OF SINUS NODE AUTOMATICITY

Three Key Ion Channels in SA Node

• Open for only a few 10,000ths of a second
• Responsible for the rapid upstroke spike in ventricular/atrial action potentials
• In SA node: almost entirely inactivated (because the resting membrane potential of -55 to -60 mV is not negative enough to de-inactivate them; fast Na⁺ channels need at least -70 mV to be fully available)

• Take 10-20× longer to open and inactivate than fast Na⁺ channels
• Conduct both Ca²⁺ and Na⁺ into the fiber when open
• Responsible for the upstroke of the SA node action potential
• Also responsible for maintaining the plateau in ventricular muscle

• Allow K⁺ to flow out of the cell
• Open during phase 3 repolarization
• Gradually close during diastole → contributes to slow depolarization (pacemaker potential)

The Pacemaker Potential (Prepotential / Phase 4 Spontaneous Depolarization)

• After each action potential, K⁺ channels are open → K⁺ flows out → membrane repolarizes to about -55 to -60 mV

• After repolarization, special HCN (hyperpolarization-activated cyclic nucleotide-gated) channels open
• These "funny" channels carry inward Na⁺ (and some K⁺) current when the membrane is hyperpolarized
• This causes the membrane potential to slowly drift upward (less negative) - this slow upward drift is the prepotential or pacemaker potential

• As membrane potential drifts toward ~-50 mV, T-type (transient) Ca²⁺ channels open
• Ca²⁺ inflow accelerates the rate of depolarization

• When membrane potential reaches threshold (~-40 mV), L-type Ca²⁺ channels open fully
• Rapid Ca²⁺ (and some Na²⁺) inflow → action potential upstroke
• Note: NO fast Na⁺ channel-dependent rapid upstroke (those are inactivated)
• Action potential reaches +10 to +20 mV

• L-type Ca²⁺ channels gradually inactivate
• K⁺ channels open (I_K) → K⁺ efflux → rapid repolarization back to -55 to -60 mV
• Cycle repeats automatically

The Slow Drift (Prepotential) is the Key to Rhythmicity

• The slow upward drift of the membrane potential from -55 mV back to the threshold of -40 mV (-40 mV) is called the pacemaker potential
• This continuous, automatic, rhythmical drifting is what makes the SA node the pacemaker
• The rate of this drift determines the heart rate

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SECTION 4: CONDUCTION OF THE CARDIAC IMPULSE THROUGH THE HEART

From SA Node → Atria → AV Node

• Impulse spreads from SA node through the internodal pathways (three recognized tracts: anterior, middle [Wenckebach], and posterior [Thorel]) to the AV node
• Total conduction time SA node → AV node: ~0.03 seconds
• Impulse also spreads through the atrial muscle in all directions
• Entire atrium depolarized in about 0.08-0.09 seconds after SA node discharge

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SECTION 5: AV NODE - DELAY AND ITS IMPORTANCE

Anatomy

• Located in the posterior wall of the right atrium, immediately behind the tricuspid valve
• Transmission through AV node and Bundle of His delayed ~0.09 seconds (total AV delay)
• Most of the delay occurs in the transitional fibers entering the AV node (very small diameter, low excitability, slow conduction of 0.02-0.05 m/sec)

Why AV Delay is Critical

1. The atria to contract first and complete ventricular filling before the ventricles contract
2. Without this delay: atria and ventricles would contract almost simultaneously → no atrial "booster pump" effect → reduced ventricular filling → reduced cardiac output

The AV Node as a Gatekeeper

• During rapid atrial rates (e.g., atrial flutter at 250-350/min), the AV node blocks some impulses
• Acts as a frequency filter - prevents all rapid atrial impulses from reaching the ventricles
• Protects ventricles from excessively fast rates that would compromise pumping

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SECTION 6: TRANSMISSION THROUGH THE BUNDLE BRANCHES AND PURKINJE SYSTEM

Bundle of His (AV Bundle)

• Passes from AV node through the fibrous barrier separating atria from ventricles
• This fibrous barrier is the only route for electrical impulse transmission from atria to ventricles (under normal circumstances)
• After passing through fibrous barrier, AV bundle divides into:
  • Left bundle branch (splits further into anterior and posterior fascicles)
  • Right bundle branch
• Both run down either side of the interventricular septum toward the apex

Purkinje Fibers

• After traversing the septum, fibers spread throughout the subendocardial surfaces of both ventricles
• Largest cardiac fibers in the heart - 70-80 μm diameter
• Highly permeable gap junctions → allow very rapid conduction: 1.5-4.0 m/sec (about 6× faster than normal ventricular muscle)
• Impulse reaches all endocardial surfaces of the ventricles within 0.03 seconds of entering the bundle branches

Why Rapid Conduction Through Purkinje System Matters

• All parts of the ventricles need to contract nearly simultaneously
• If conduction were via ventricular muscle alone (slow, 0.3-0.5 m/sec): sequential, non-simultaneous contraction → inefficient pumping
• Rapid Purkinje conduction → near-simultaneous contraction of all ventricular muscle → maximum pressure development

Sequence of Ventricular Activation

1. Impulse enters the interventricular septum from the left → septal depolarization first (left to right)
2. Purkinje fibers carry impulse rapidly to endocardial surfaces of both ventricles
3. Depolarization spreads from endocardium outward through ventricular muscle to epicardium
4. Apex and lateral walls depolarize before the base
5. Last to depolarize: basal portions and posterolateral wall of left ventricle and pulmonary conus

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SECTION 7: THE SA NODE AS THE NORMAL PACEMAKER

Intrinsic Rates of Potential Pacemakers

Why SA Node Controls the Heart Rate

• SA node has the fastest intrinsic rate of spontaneous depolarization
• It reaches threshold and fires before any other potential pacemaker
• When SA node fires, its action potential spreads through the entire heart - including the AV node and Purkinje fibers - resetting those cells before they can fire spontaneously
• The SA node thus continuously "overdrive suppresses" all lower pacemakers

Overdrive Suppression

• Any pacemaker that is stimulated at a rate faster than its intrinsic rate is suppressed
• The faster the overdrive rate, the more Na⁺/K⁺-ATPase pumps Na⁺ out and hyperpolarizes the cell
• If SA node suddenly fails: lower pacemaker is suppressed → brief pause → then lower pacemaker eventually "escapes" and takes over at its own slower intrinsic rate

Ectopic Pacemakers

• Any region of the heart that develops abnormal automaticity and fires faster than the SA node can take control = ectopic pacemaker or ectopic focus
• Causes: ischemia, electrolyte imbalances (especially hypokalemia), digitalis toxicity, excess catecholamines
• Ectopic beats emanating from below SA node produce abnormal conduction patterns visible on ECG

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SECTION 8: ROLE OF THE PURKINJE SYSTEM IN CAUSING NORMAL VENTRICULAR CONTRACTION

1. Synchronous activation of ventricular muscle for maximum pumping efficiency
2. Ensures endocardial-to-epicardial activation direction → depolarization wave front moves from inside to outside of ventricular wall

• Impulse must travel through ventricular muscle (slow, 0.3-0.5 m/sec)
• Activation becomes sequential rather than simultaneous
• QRS complex widens (>0.12 sec)
• Pumping efficiency reduced

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SECTION 9: AUTONOMIC CONTROL OF HEART RHYTHMICITY AND CONDUCTION

Parasympathetic (Vagal) Stimulation

• Releases acetylcholine at vagal nerve endings
• Slows SA node discharge rate
• Decreases excitability of AV junctional fibers → slows/blocks AV conduction

1. ACh binds M₂ muscarinic receptors on SA/AV nodal cells
2. Activates I_KACh (acetylcholine-activated K⁺ current) via G-protein (Gᵢ)
3. Increased K⁺ permeability → rapid K⁺ efflux → hyperpolarization
4. In SA node: resting potential becomes -65 to -75 mV (vs. normal -55 to -60 mV)
   • More negative starting point → slow upward drift takes longer to reach threshold → slower rate
   • Strong enough vagal stimulation → cannot reach threshold → sinus arrest
5. In AV node: hyperpolarization → decreased excitability → less likely that small atrial impulses can excite nodal fibers → conduction delay or block

Sympathetic Stimulation

1. Increases SA node discharge rate (positive chronotropy)
2. Increases conduction velocity throughout the heart (positive dromotropy)
3. Increases excitability in all portions of the heart
4. Increases force of contraction (positive inotropy - see Chapter 9)

• Almost triple heartbeat frequency (up to ~180-200 bpm)
• Increase contractile strength up to 2-fold

1. Norepinephrine released at sympathetic nerve endings → binds β₁-adrenergic receptors
2. Activates Gs → increases cAMP → activates PKA
3. In SA node:
   • Increases permeability to Na⁺ and Ca²⁺
   • Resting potential becomes more positive (less negative) → closer to threshold
   • Rate of upward drift of diastolic membrane potential increases → threshold reached sooner → faster heart rate
   • I_f (funny current / HCN channels) activated → accelerates pacemaker potential
4. In AV node and Purkinje system:
   • Increased excitability → faster conduction
5. In ventricular muscle:
   • More Ca²⁺ entry and enhanced Ca²⁺ release from SR → stronger contraction

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SECTION 10: ABNORMAL RHYTHMS - OVERVIEW

Heart Block

• SA nodal block: impulses fail to leave SA node → bradycardia or sinus arrest
• First-degree AV block: PR interval prolonged (>0.2 sec) but every impulse conducted
• Second-degree AV block: some impulses blocked at AV node (e.g., 2:1 - every other P wave conducts)
• Third-degree (complete) AV block: no atrial impulses reach ventricles
  • Ventricles "escape" at their own idioventricular rate of 15-40 bpm (very slow)
  • Patient may develop Stokes-Adams syndrome (fainting attacks from insufficient cardiac output)
  • Treatment: artificial cardiac pacemaker

Purkinje System Block

• Block in the left or right bundle branch → bundle branch block
• Impulse must travel through slow ventricular muscle from the unblocked side
• Delayed activation of one ventricle → widened QRS (>0.12 sec)
• Both ventricles still eventually depolarize
• Left bundle branch block more clinically significant (larger LV mass)

Premature Contractions (Extrasystoles)

• Caused by ectopic foci anywhere in the heart
• After an extrasystole, a compensatory pause occurs (next SA impulse arrives when ventricle is still refractory from the extrasystole → ventricle skips one beat)
• Causes of ectopic beats: caffeine, nicotine, lack of sleep, anxiety, ischemia, electrolyte disorders, digitalis toxicity

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SECTION 11: CARDIAC RESYNCHRONIZATION THERAPY (CRT) - Clinical Application

• In heart failure with left bundle branch block: both ventricles do not contract simultaneously
• Left ventricle contracts late → reduces pumping efficiency
• Biventricular pacing (CRT): paces both ventricles simultaneously to restore synchrony
• Improves cardiac output, reduces heart failure symptoms
• Demonstrated survival benefit in selected patients with:
  • Reduced ejection fraction (EF ≤35%)
  • Wide QRS (≥130-150 ms, especially with LBBB morphology)
  • Symptomatic heart failure despite optimal medical therapy

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KEY NUMBERS TO REMEMBER - CHAPTER 10

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GUYTON & HALL - TEXTBOOK OF MEDICAL PHYSIOLOGY

CHAPTER 11: The Normal Electrocardiogram

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OVERVIEW

• Cardiac arrhythmias
• Myocardial infarction and ischemia
• Ventricular hypertrophy
• Bundle branch blocks
• Electrolyte abnormalities

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SECTION 1: WAVEFORMS OF THE NORMAL ECG

The Three Main Components

The QRS Complex

• Often (but not always) three separate waves:
  • Q wave - first downward deflection before the R wave; small negative wave
  • R wave - large upward (positive) deflection
  • S wave - downward deflection after R wave
• Not every QRS complex has all three components visible in every lead

Normal Intervals and Durations

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SECTION 2: DEPOLARIZATION WAVES vs. REPOLARIZATION WAVES - The Fundamental Distinction

Depolarization Wave (e.g., QRS)

• As depolarization spreads from left to right across a muscle fiber:
  • The leading (already depolarized) area = negative outside
  • The trailing (still polarized) area = positive outside
  • Electrode near the positive end records a positive deflection
  • When depolarization is complete: both ends equally depolarized → returns to zero

Repolarization Wave (e.g., T wave)

• As repolarization spreads from left to right across a muscle fiber:
  • The leading (already repolarized) area = positive outside
  • The trailing (still depolarized) area = negative outside
  • Opposite polarity from the depolarization wave
  • Electrode near the leading end records a negative deflection

Why the T Wave Is Upright (Same Direction as QRS) in Normal Hearts

• In normal ventricular muscle, repolarization occurs in the opposite order from depolarization
• Depolarization: endocardium → epicardium (inner to outer)
• Repolarization: epicardium → endocardium (outer to inner, because epicardial action potentials are shorter)
• Because repolarization travels in the reverse direction from depolarization, its polarity is again the same as the QRS (positive end still toward the apex)
• Net result: T wave is concordant (same direction) with QRS in normal hearts

Relation of Monophasic Action Potential to QRS and T Waves

• QRS begins when ventricular muscle depolarizes
• ST segment corresponds to the plateau of the action potential (isoelectric because all cells are equally depolarized - no current flowing between cells)
• T wave corresponds to repolarization as cells return to resting potential

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SECTION 3: CURRENT FLOW IN THE CHEST AROUND THE HEART

How Currents Reach the Body Surface

• From the depolarized (negative) area
• To the still-polarized (positive) area
• In large circuitous routes through body fluids

Direction of Current Flow During Ventricular Depolarization

1. Cardiac impulse arrives first in the septum (left endocardium of septum first)
2. Spreads to inner surfaces of both ventricles (endocardial surfaces)
3. This creates: electronegativity on inside, electropositivity on outer ventricular walls
4. Current flows through body fluids along elliptical paths
5. Algebraic average of all current flows = current predominantly directed from base toward apex (base = negative end, apex = positive end)
6. This remains true for most of ventricular depolarization
7. Exception: Very end of depolarization - last areas to depolarize are the outer walls near the ventricular base → current briefly reverses (~0.01 sec)

• Electrode nearer the base = negative
• Electrode nearer the apex = positive
• Recording meter shows a positive deflection (R wave in most leads)

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SECTION 4: THE ELECTROCARDIOGRAPHIC LEADS

Three Standard Bipolar Limb Leads

Lead I + Lead III = Lead II (At any instant, the sum of the voltages in leads I and III equals the voltage in lead II. This is a mathematical consequence of the geometry of Einthoven's triangle.)

• Lead I: Positive P wave, positive QRS (upright R), positive T wave
• Lead II: All waves positive and largest (axis of lead closest to mean cardiac vector of +60°)
• Lead III: Variable; P and T waves usually positive; QRS may be positive, biphasic, or negative

Precordial (Chest) Leads: V1-V6

• Positive electrode: placed on anterior chest wall at six standard positions
• Negative (indifferent) reference electrode (Wilson's Central Terminal): connected through equal resistances to RA, LA, and LL simultaneously (creates a near-zero reference)

Electrode Positions:

QRS Morphology in Chest Leads:

• V1, V2 (near the base): QRS mainly negative - electrode is closer to the base, which is the direction of electronegativity during most depolarization
• V4, V5, V6 (near the apex): QRS mainly positive - electrode is closer to the apex (direction of electropositivity during most depolarization)
• V3 = transitional zone - QRS is biphasic (equiphasic)
• R wave progression: R wave should grow progressively taller from V1 to V5/V6 (poor R wave progression suggests anterior MI or LV dysfunction)

Augmented (Unipolar) Limb Leads: aVR, aVL, aVF

• aVR: Inverted (negative) P, QRS, and T - because positive electrode is on the right arm which "looks away" from the cardiac apex (the heart's electrical mean vector points away from aVR's positive electrode)
• aVL: Similar to Lead I
• aVF: Similar to Lead II; all waves usually positive (positive electrode at foot, looks up toward cardiac apex)

The 12-Lead ECG: Summary of All 6 Limb + 6 Chest Leads

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SECTION 5: THE NORMAL ECG WAVEFORM DETAILS

P Wave

• Cause: Depolarization spreading from SA node through the atria
• Duration: ~0.08-0.10 sec
• Amplitude: Small (atrial muscle mass is small)
• In lead II: upright, rounded, smooth
• Normally < 0.12 sec wide and < 2.5 mm tall

PR Interval

• From onset of P wave to onset of QRS complex
• Represents: atrial depolarization + AV nodal delay + Bundle of His conduction
• Normal: 0.12-0.20 sec (120-200 ms)
• Mostly represents the AV nodal delay (~0.09 sec of the total)
• Shortens with faster heart rates; lengthens with slower rates

QRS Complex

• Cause: ventricular depolarization
• Normal duration: 0.06-0.10 sec (60-100 ms)

• 0.12 sec (120 ms) = abnormal ("wide QRS"), suggests bundle branch block or ventricular origin

Q Wave:

• Small initial negative deflection in some leads
• Represents initial septal depolarization (left to right, away from most electrodes)
• Pathological Q wave: > 0.04 sec wide or > 25% of R wave height = suggests prior MI
• Normal septal Q waves: small, narrow, in leads I, aVL, V5, V6

R Wave:

• Main upward deflection
• Largest component in most leads
• Height depends on the magnitude of ventricular muscle mass and proximity of electrode

S Wave:

• Terminal downward deflection
• Represents late ventricular depolarization (basal portions of LV)

ST Segment

• From end of QRS to beginning of T wave
• Represents: period when all ventricular muscle is depolarized (plateau phase of action potential)
• Normal: isoelectric (flat at baseline) → no voltage difference between any ventricular areas
• ST elevation: Injury (early MI, Prinzmetal angina, pericarditis)
• ST depression: Subendocardial ischemia, reciprocal change

T Wave

• Cause: ventricular repolarization
• Occurs 0.25-0.35 sec after depolarization
• Normally upright in leads I, II, V3-V6 (concordant with QRS because of epicardial-to-endocardial repolarization)
• Normally inverted (negative) in aVR
• Variable in III, aVL, V1, V2

U Wave

• Small wave after T wave (not always present)
• Thought to represent repolarization of Purkinje fibers or mid-myocardial cells
• Prominent U waves: seen in hypokalemia

QT Interval

• From onset of QRS to end of T wave
• Represents total duration of ventricular depolarization + repolarization
• Normal: 0.35-0.44 sec (varies inversely with heart rate - shortens at faster rates)
• Corrected QT interval: QTc = QT / √RR (Bazett's formula)
  • QTc > 0.44-0.45 sec = prolonged → risk of fatal arrhythmias (torsades de pointes)

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SECTION 6: RECORDING SYSTEMS AND PAPER

ECG Paper

• Standard speed: 25 mm/sec
• Small squares: 1 mm × 1 mm = 0.04 sec horizontally; 0.1 mV vertically (at standard calibration of 1 mV/10 mm)
• Large squares: 5 mm × 5 mm = 0.2 sec horizontally; 0.5 mV vertically
• Standard calibration: 1 mV = 10 mm deflection (shown as calibration pulse at start of tracing)

Calculating Heart Rate from ECG

• Count the number of large squares (each = 0.2 sec) between two consecutive R waves
• Heart rate = 300 / number of large squares between R waves
• Or: count QRS complexes in 6-second strip × 10 = rate per minute

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SECTION 7: CLINICAL CORRELATION - WHAT CHANGES THE ECG

Abnormalities Visible on the Normal Baseline ECG

• Left ventricular hypertrophy (LVH): Increased QRS voltage (tall R in V5/V6, deep S in V1), left axis deviation, ST-T changes (strain pattern)
• Right ventricular hypertrophy (RVH): Tall R in V1, right axis deviation, inverted T in V1-V3

• Ischemia: ST depression, T wave inversion
• Acute injury (STEMI): ST elevation
• Old infarct: Pathological Q waves

• Hyperkalemia: Peaked T waves → wide QRS → sine wave pattern
• Hypokalemia: Flat/inverted T waves, prominent U waves, prolonged QT
• Hypercalcemia: Shortened QT
• Hypocalcemia: Prolonged QT

• Visible as changes in rate, regularity, P wave morphology, PR interval, QRS width

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SECTION 8: NORMAL ECG AXIS AND MEAN CARDIAC VECTOR

The Mean QRS Axis

• Normal axis: approximately +59° (pointing downward and to the left, toward the apex)
• This means during most of ventricular depolarization, the apex remains positive relative to the base

Normal Axis Range:

• Normal: -30° to +90°
• Left axis deviation (LAD): more negative than -30° → suggests LVH, left anterior fascicular block
• Right axis deviation (RAD): more positive than +90° → suggests RVH, left posterior fascicular block, dextrocardia

Why the Normal Axis Is Around +59°

• The left ventricle is larger and depolarizes slightly later
• The predominant direction of depolarization wave front moves down and to the left toward the apex of the left ventricle

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KEY NUMBERS TO REMEMBER - CHAPTER 11

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GUYTON & HALL - TEXTBOOK OF MEDICAL PHYSIOLOGY

CHAPTER 12: Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis

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OVERVIEW

1. The concept of vectors representing cardiac electrical potentials
2. How to determine the mean electrical axis of the ventricles
3. How to interpret abnormal axis deviations
4. How the ECG changes with ventricular hypertrophy
5. How ischemia, injury, and infarction alter the ECG
6. The current of injury concept and its use in diagnosing MI

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SECTION 1: VECTORS REPRESENTING ELECTRICAL POTENTIALS

What Is a Vector?

• A vector is an arrow that:
  • Points in the direction of the electrical potential generated by current flow
  • Has the arrowhead at the positive end
  • Has a length proportional to the voltage of the potential

Instantaneous Mean Vector

• Current flows predominantly from base toward apex (base = negative, apex = positive)
• The instantaneous mean vector points from base to apex
• This is a long vector (large current, large voltage)

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SECTION 2: THE DIRECTION OF A VECTOR IN DEGREES - THE REFERENCE SYSTEM

Degree Convention (Frontal Plane)

Normal Mean QRS Vector

• The average direction of the vector during spread of the depolarization wave through the ventricles = mean QRS vector
• Normal mean QRS vector = approximately +59° (pointing downward and to the left, toward the cardiac apex)
• This means: during most ventricular depolarization, the apex remains positive relative to the base

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SECTION 3: AXES OF THE STANDARD LEADS

How a Vector Projects onto a Lead

• When the heart vector points in the same direction as a lead's axis → maximum positive recording in that lead
• When the heart vector is perpendicular to a lead's axis → zero (isoelectric) in that lead
• When the heart vector points away from a lead's positive electrode → negative recording

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SECTION 4: VECTORCARDIOGRAM

Definition

• As depolarization sweeps through the ventricles, the instantaneous mean vector changes both magnitude and direction
• Plotting the tip of this changing vector traces a loop

QRS Loop

• Represents the changing mean vector during ventricular depolarization
• Begins at center (zero), sweeps outward (increasing voltage), then returns to center (all depolarized)
• The loop for a normal heart is oriented mainly in the +40° to +70° direction (downward-left)

T Loop

• Represents the changing mean vector during ventricular repolarization
• In the normal heart: T loop is oriented in approximately the same direction as the QRS loop
• This is why the T wave is concordant (same polarity) with the QRS complex in most leads

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SECTION 5: DETERMINING THE MEAN ELECTRICAL AXIS FROM STANDARD LEADS

Clinical Method (Using Leads I and III)

• Net QRS = positive area minus negative area of the QRS
• If the QRS is entirely positive, net potential = total positive amplitude
• If part is negative, subtract the negative area from the positive area

• On the lead I axis (horizontal line at 0°): plot the net voltage of lead I
• On the lead III axis (+120°): plot the net voltage of lead III

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SECTION 6: NORMAL AXIS AND AXIS DEVIATIONS

Normal Range

• Normal mean electrical axis: -30° to +90°
• Most commonly +59° in normal adults

Axis Deviations and Their Causes

Physiological Causes of Normal Axis Variation

• Normal hearts: axis may vary from about +20° to +100° depending on:
  • Anatomical differences in Purkinje distribution
  • Body position (lying vs. standing)
  • Body habitus (obese = more horizontal = more leftward; tall, thin = more vertical = more rightward)
  • Inspiration vs. expiration (inspiration lowers diaphragm → heart more vertical → RAD tendency)

Change in Heart Position in the Chest

• Heart tipped to the left (e.g., during expiration, obesity, pregnancy): mean electrical axis swings toward left axis deviation
• Heart tipped to the right (e.g., during inspiration, tall/thin person): mean electrical axis swings toward right axis deviation
• These are purely positional changes, NOT pathological

Left Ventricular Hypertrophy (LVH) Causing LAD

• LV massively enlarged → greater electrical potentials generated by larger LV muscle mass
• Mean QRS vector swings further to the left and slightly upward
• In extreme LVH: axis may reach -20° to -30° (left axis deviation)
• Also: increased QRS voltage, prolonged QRS duration (longer travel path through larger muscle mass)

Right Ventricular Hypertrophy (RVH) Causing RAD

• Normal RV generates only 25% of the total QRS vector (much smaller than LV)
• In RVH: RV mass increases dramatically relative to LV
• RV vectors now dominate → mean QRS vector shifts to the right, often to +110° to +180°
• ECG: tall R wave in V1, deep S wave in V5/V6, right axis deviation

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SECTION 7: BUNDLE BRANCH BLOCK AND QRS CHANGES

Complete Left Bundle Branch Block (LBBB)

• Left bundle branch blocked → LV depolarizes late via slower conduction through ventricular muscle
• Right ventricle depolarizes first (normally)
• Then depolarization spreads slowly through left ventricular muscle from right to left
• Result:
  • QRS duration ≥ 0.12 sec (widened)
  • Mean QRS vector swings to the left (because LV depolarizes last and predominates)
  • Left axis deviation common
  • Wide, notched R wave in leads I and aVL ("M" shape or "RSR' pattern")
  • Wide, deep S wave in leads V1 and V2

Complete Right Bundle Branch Block (RBBB)

• Right bundle branch blocked → RV depolarizes late via slow spread through ventricular muscle
• LV depolarizes first (normally)
• Then depolarization spreads slowly through RV from left to right
• Result:
  • QRS duration ≥ 0.12 sec (widened)
  • Mean QRS vector may swing to the right (because RV depolarizes last)
  • RSR' pattern in V1 ("rabbit ears" or "M-shaped" QRS in V1)
  • Wide, deep S wave in leads I, V5, V6
  • RBBB is often benign; LBBB more commonly associated with serious disease

Purkinje System Block Prolongs QRS

• Any block in the Purkinje system → impulse must travel slowly through ventricular muscle
• Slows overall ventricular conduction → widens QRS beyond 0.12 sec
• Also causes the heart vector to remain pointed in one direction for a longer time during the slowly conducting portion
• This creates the tall, bizarre QRS patterns seen in bundle branch blocks

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SECTION 8: VENTRICULAR VOLTAGE AND QRS AMPLITUDE

Increased QRS Voltage

• Normal amplitude of QRS in standard leads: about 1 mV peak-to-peak (varies widely)
• QRS voltage increases when:
  1. Hypertrophy of ventricular muscle → more muscle mass generating more current
  2. Thin chest wall → electrodes closer to the heart
  3. Increased conductance of surrounding tissues

• S wave in V1 + R wave in V5 or V6 > 35 mm (3.5 mV)
• R wave in aVL > 11 mm (1.1 mV)
• R wave in lead I > 15 mm

Decreased QRS Voltage

1. Multiple old myocardial infarcts (cardiomyopathy):
   • Loss of muscle mass → less current generated → lower voltage
   • Depolarization wave slows through fibrotic areas → prolonged QRS simultaneously
   • Low-voltage ECG with wide QRS = classic pattern after multiple MIs
2. Infiltrative myocardial disease:
   • Cardiac amyloidosis: Abnormal proteins infiltrate myocardium
   • Classic pattern: low voltage in limb leads despite possibly increased wall thickness (due to amyloid deposition)
   • Discordance between echo wall thickness and ECG voltage is a hallmark of amyloidosis
3. Pericardial effusion:
   • Extracellular fluid in pericardial sac = highly conductive
   • "Short-circuits" electrical potentials - current flows through pericardial fluid instead of reaching chest wall electrodes
   • Dramatically reduces ECG voltages in all leads
   • Large enough effusion → electrical alternans (alternating QRS axis/voltage with each beat as heart swings in fluid)
4. Pleural effusion:
   • Same mechanism but less pronounced than pericardial effusion
   • Fluid around lungs short-circuits electricity to body surface
5. Pulmonary emphysema:
   • Increased air content in lungs → air is a poor electrical conductor (insulator)
   • Lungs envelop heart to a greater extent
   • Prevents spread of electrical voltage from heart to body surface
   • Results in decreased ECG potentials in all leads

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SECTION 9: PROLONGED AND BIZARRE QRS PATTERNS

Prolonged QRS (> 0.12 sec) - Causes

1. Ventricular hypertrophy or dilation:
   • Larger muscle mass → longer path for depolarization wave to travel
   • Normal QRS: 0.06-0.08 sec
   • In hypertrophy/dilation: can reach 0.09-0.12 sec
2. Bundle branch block:
   • Impulse must travel through slow ventricular muscle
   • QRS: typically 0.14-0.20 sec
3. Premature ventricular contractions (PVCs):
   • Ectopic impulse originates in ventricular muscle (not Purkinje system)
   • Spreads entirely through slow ventricular muscle
   • QRS extremely wide and bizarre
4. Multiple old infarcts with fibrosis:
   • Multiple areas of slow conduction
   • QRS prolonged + low voltage

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SECTION 10: CURRENTS OF INJURY - THE ECG OF ISCHEMIA AND INFARCTION

The Concept of Current of Injury

• Injured muscle remains partially or fully depolarized even during diastole
• While surrounding normal muscle is repolarized and polarized (resting potential)
• This creates a voltage difference between injured and normal areas during diastole
• Current flows from the polarized (normal) area to the depolarized (injured) area during diastole = "current of injury"

How the Current of Injury Distorts the ECG Baseline

• Current of injury flows continuously during diastole (between beats)
• The true baseline (T-P segment) shifts due to this injury current
• However, the ECG machine continuously re-zeros itself around this shifted baseline
• The net result appears as a displacement of the ST segment relative to the T-P segment
• Positive injury potential (normal tissue near recording electrode, injured tissue away) → ST elevation in that lead
• Negative injury potential (injured tissue near recording electrode) → ST depression in that lead

The J Point - Zero Reference for Injury Potentials

• The J point = the exact moment when ventricular depolarization is complete (end of QRS)
• At the J point: ALL ventricular muscle is depolarized (normal + injured) → no current of injury flowing → this instant = true zero potential
• A horizontal line drawn through the J point = the zero voltage baseline
• Injury potential in any lead = the difference between the T-P segment level and the J-point baseline

Using J Point to Analyze the Injury Vector

1. Draw horizontal line through J point in each lead (= true zero)
2. Measure the injury potential above or below this line in leads I and III
3. Plot these on the lead axes
4. Draw perpendiculars from the tips
5. The intersection = apex of the injury potential vector
6. The vector points from injured (negative) area to normal (positive) area

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SECTION 11: ECG CHANGES IN MYOCARDIAL INFARCTION

Stages of ECG Changes After Acute MI

ST Elevation in Acute MI (STEMI)

• The acutely injured muscle is depolarized even during diastole → current of injury
• Leads facing the infarcted wall show ST elevation
• Leads on the opposite wall show reciprocal ST depression

• ST elevation in V1-V4 (anterior chest leads)
• Reciprocal ST depression in II, III, aVF

• ST elevation in II, III, aVF
• Reciprocal ST depression in I, aVL, V1-V3

• ST elevation in I, aVL, V5, V6

• Reciprocal ST depression in V1-V3 (because posterior wall is far from anterior leads)
• Tall R waves in V1, V2 (mirror image of Q waves that would appear from the back)

Current of Injury: Anterior vs. Posterior Wall Infarction

• Injury vector points anteriorly (toward the normal posterior wall and away from the injured anterior wall)
• Chest lead facing anterior wall: injury potential negative (below J-point baseline) → this appears as ST elevation in the clinical convention
• (Note: Guyton explains this from first principles - the positive end of the injury vector points to normal tissue)

• Injury potential negative in leads II and III (posterior infarct at apex)
• Vectorial analysis: resultant injury vector ~-95° (negative end pointing downward toward injured apex)
• Helps localize the infarct to the posterior-apical portion of LV

Permanent Q Waves After MI

• Dead muscle = electrically silent (no action potentials)
• Creates an electrical "window" in the ventricular wall
• Electrodes "looking through" this window record the opposite wall's potentials as negative
• Results in pathological Q waves in leads facing the infarcted area
• Q waves persist for life as a permanent marker of old MI

• Q waves develop in Lead I (or V1-V4) due to loss of anterior LV muscle

• Q waves develop in Lead III (and II, aVF) due to loss of posterior-apical muscle

Characteristics of Pathological Q Waves:

• Duration ≥ 0.04 sec (40 ms)
• Amplitude ≥ 25% of the R wave height in the same lead
• (Normal small septal q waves: narrow, < 0.04 sec, < 25% R wave height)

Progressive ECG Recovery After MI (Fig 12.21 pattern)

• Day 1: Strong injury current (ST elevation or T-P displacement)
• ~1 week: Injury potential diminishing
• 3 weeks: Injury potential gone; Q waves remain
• 1 year: Stable ECG with Q waves; recovery via new collateral coronary flow
• If blood supply never adequately restored → injury potential persists indefinitely (especially during exercise)

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SECTION 12: ANGINA PECTORIS AND ECG DURING ISCHEMIA

Angina Pectoris

• "Angina pectoris" = chest pain from heart ischemia, felt in the pectoral region
• Typically radiates to left neck and down the left arm
• Caused by moderate-to-severe ischemia of the heart muscle
• Usually absent at rest; appears when heart is overworked (exercise, stress)

ECG During Angina Attack

• During ischemia: injured muscle produces a current of injury
• Manifests as:
  • ST depression (subendocardial ischemia - most common type)
  • ST elevation (transmural ischemia, as in Prinzmetal's variant angina from coronary spasm)
  • T wave inversion in leads facing ischemic area
• ECG returns to normal when ischemia resolves (unlike in MI where Q waves are permanent)
• Exercise stress test deliberately provokes ischemia to detect these changes

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SECTION 13: EFFECT OF SLOW CONDUCTION ON T WAVE (CONNECTION TO CHAPTER CONTENT)

Why T Wave Is Normally Concordant with QRS

• Ventricular depolarization: endocardium → epicardium (slow via Purkinje + muscle)
• Ventricular repolarization: epicardium → endocardium (epicardial cells repolarize first - shorter action potentials)
• Because repolarization travels in the reverse direction from depolarization → same polarity appears in each lead → T wave upright where QRS is upright

When Slow Conduction Distorts the T Wave

• If one ventricle or region is slow to depolarize (e.g., bundle branch block):
  • Areas that depolarized late also repolarize late
  • Repolarization sequence becomes distorted
  • T wave axis may no longer be concordant with QRS
  • T wave inversion or biphasic T waves appear in certain leads
• In bundle branch block: T waves are typically discordant (opposite direction) to the main QRS deflection
  • E.g., in LBBB: large positive R in V5/V6 → T wave inverted in V5/V6 (secondary repolarization abnormality)

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KEY NUMBERS TO REMEMBER - CHAPTER 12

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GUYTON & HALL - TEXTBOOK OF MEDICAL PHYSIOLOGY

CHAPTER 15: Vascular Distensibility and Functions of the Arterial and Venous Systems

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OVERVIEW

1. Vascular distensibility and compliance - how vessels expand and store blood
2. Arterial pressure pulsations - the generation, characteristics, and transmission of pulse pressure
3. Venous functions - venous pressure, the venous pump, and blood reservoir role of veins

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SECTION 1: VASCULAR DISTENSIBILITY

Definition and Formula

Vascular distensibility = Increase in volume / (Increase in pressure × Original volume)

• Units: fraction per mm Hg (or % per mm Hg)
• Example: If 1 mm Hg pressure rise causes a vessel originally containing 10 mL to expand by 1 mL → distensibility = 1/10 = 0.1 per mm Hg = 10% per mm Hg

Veins Are Far More Distensible Than Arteries

• Arterial walls are thick and strong (contain more elastin and collagen) to withstand high systolic pressure
• Venous walls are thin and compliant because they operate at low pressures

• Arteries act as a pressure reservoir (Windkessel effect)
• During systole: arteries distend to accept the stroke volume → store pressure
• During diastole: artery walls recoil → continue to push blood forward
• Result: converts pulsatile cardiac output into a more continuous flow through capillaries

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SECTION 2: VASCULAR COMPLIANCE (CAPACITANCE)

Definition and Formula

Vascular compliance = Increase in volume / Increase in pressure

Compliance vs. Distensibility - Critical Distinction

Compliance = Distensibility × Volume

• A vessel can be highly distensible but have low compliance if it has a very small volume
• Conversely: a less distensible vessel with a large volume can have high compliance

• Veins are 8× more distensible than arteries AND have ~3× more volume
• Therefore, venous compliance = 8 × 3 = 24× greater than arterial compliance

Volume-Pressure Curves of the Systemic Circulation

• Normal filling (~700 mL) → mean arterial pressure ~100 mm Hg
• At only 400 mL → pressure falls to zero
• Relatively small volume changes → large pressure changes (low compliance)
• The arterial curve is steep (small volume range, large pressure range)

• Normal filling: 2,000-3,500 mL of blood
• Change of several hundred mL is required to change venous pressure by only 3-5 mm Hg
• This explains why 500 mL blood transfusion can be given in minutes without greatly altering circulatory function
• The venous curve is flat (large volume range, small pressure change)

Effect of Sympathetic Stimulation on Volume-Pressure Curves

• Sympathetic stimulation → increases vascular smooth muscle tone → arteries and veins contract → pressure increases at same volume (curve shifts up and left)
• Sympathetic inhibition → vascular relaxation → pressure decreases at same volume (curve shifts down and right)
• This gives the nervous system powerful control over blood distribution and venous return
• During hemorrhage: sympathetic activation constricts veins → maintains venous return and cardiac output despite blood loss

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SECTION 3: ARTERIAL PRESSURE PULSATIONS

Why Pulsations Occur

Normal Arterial Pressure Values (Young Adult at Rest)

Pulse Pressure - Definition and Determinants

Pulse pressure = Systolic pressure - Diastolic pressure

Pulse pressure ≈ Stroke volume / Arterial compliance

• Greater SV → more blood enters arteries per beat → greater pressure rise → wider pulse pressure
• Example: exercise increases SV → increases pulse pressure

• Less compliant (stiffer) arteries → same SV causes a greater pressure rise → wider pulse pressure
• Example: arteriosclerosis → stiff arteries → increased pulse pressure

• Increased pulse pressure: arteriosclerosis, aortic regurgitation, patent ductus arteriosus, high fever (vasodilation), exercise
• Decreased pulse pressure: aortic stenosis, heart failure (reduced SV), hypovolemia

Mean Arterial Pressure (MAP)

• At normal heart rates (~72 bpm), the heart spends more time in diastole than systole
• Therefore, pressure stays closer to diastolic for a greater part of each cycle

MAP ≈ Diastolic pressure + 1/3 × Pulse pressure Or: MAP ≈ 0.6 × Diastolic + 0.4 × Systolic

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SECTION 4: ABNORMAL PRESSURE PULSE CONTOURS

Aortic Stenosis

• Narrowed aortic valve opening → restricted blood flow into aorta
• Reduced systolic pressure peak
• Slow, gradual rise to a low, rounded peak
• Narrow, flat pulse contour
• Pulse pressure is reduced
• Classic term: "pulsus parvus et tardus" (small and slow pulse)

Patent Ductus Arteriosus (PDA)

• Persistent connection between aorta and pulmonary artery
• During systole: blood ejected into aorta
• During diastole: blood rushes backward from aorta → through PDA → into pulmonary artery
• Result: diastolic pressure falls very low before the next heartbeat
• Wide pulse pressure (high systolic, very low diastolic)
• Classic: "bounding" or "water-hammer" pulse
• Pulse pressure may reach 80-100 mm Hg or more

Aortic Regurgitation (Aortic Insufficiency)

• Incompetent aortic valve → during diastole, blood leaks back from aorta into LV
• High systolic pressure (large SV because LV fills with both pulmonary venous blood + regurgitant flow)
• Very low diastolic pressure (aorta empties backward into LV)
• Extremely wide pulse pressure
• Classic signs: Corrigan's (water-hammer) pulse, Quincke's sign, pistol-shot femorals

Arteriosclerosis (Arterial Stiffening)

• Stiff, noncompliant arteries
• Same SV → much greater pressure rise in systole
• Elevated systolic pressure, normal or low-normal diastolic
• Significantly increased pulse pressure
• Pulse rises and falls steeply
• Accounts for the typical rise in systolic pressure with aging

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SECTION 5: TRANSMISSION OF PRESSURE PULSES TO PERIPHERAL ARTERIES

Damping of Pulsations Along the Vascular Tree

• Two opposing effects:
  1. Damping due to viscous resistance and vessel wall compliance → reduces pulsations
  2. Reflected waves from peripheral branches → overlap with incoming wave → can temporarily amplify the pulse in peripheral arteries
• Result: radial artery systolic pressure is slightly higher (~5-10 mm Hg) than aortic root systolic pressure (important clinically - peripheral systolic BP slightly overestimates central aortic systolic BP)
• Beyond the arterioles: wall compliance and viscous resistance damp pulsations completely → capillary flow is nearly non-pulsatile

Clinical Significance

• Capillary flow is almost entirely non-pulsatile → smooth, continuous delivery of nutrients to tissues
• Exception: some capillaries in highly vascular organs (kidneys, skeletal muscle) still show slight pulsatility

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SECTION 6: MEASUREMENT OF ARTERIAL PRESSURE

Direct (Invasive) Methods

• Catheter inserted into artery → connected to a pressure transducer
• Most accurate; used in ICU/surgery
• Can record beat-to-beat variations and waveform morphology

Auscultatory Method (Korotkoff Sounds)

1. Place sphygmomanometer cuff around upper arm
2. Place stethoscope over the brachial artery at the antecubital fossa
3. Inflate cuff above systolic pressure → brachial artery completely occluded → no sounds heard
4. Slowly deflate the cuff while listening:

• Blood jetting through the partially occluded artery in turbulent flow
• Turbulence creates vibrations of the arterial wall heard through the stethoscope
• When the artery is wide open (normal flow), laminar flow produces no sound

Automated Oscillometric Method

• Uses electronic pressure sensors instead of stethoscope
• Detects pressure oscillations in the cuff caused by pulsatile blood flow
• Maximum oscillation amplitude correlates with MAP
• Systolic and diastolic derived algorithmically
• Used in most automated blood pressure devices
• Accuracy depends on proper cuff size and patient movement

Normal Blood Pressure Values and Age-Related Changes

• Birth: ~70/40 mm Hg (low, rises rapidly in first weeks)
• Young adults (20-30 years): ~120/80 mm Hg
• With aging:
  • Systolic pressure rises progressively
  • Diastolic pressure rises until age ~50-55, then may plateau or decline
  • Pulse pressure increases with age (increasing arterial stiffness)

• Until age ~45-55: men have slightly higher BP than women (few mm Hg)
• After menopause: women's BP rises to match men's (loss of estrogen's vasodilatory effect)

• Systolic pressure rises more steeply in both sexes
• Due to progressive arterial stiffening (atherosclerosis)
• Widened pulse pressure is a marker of increased cardiovascular risk in the elderly

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SECTION 7: VEINS AND THEIR FUNCTIONS

Five Key Functions of Veins

1. Conduits - return blood from capillaries to the right heart
2. Blood reservoir - store large volumes of blood that can be mobilized as needed
3. Venous pump - propel blood toward the heart via skeletal muscle contractions + venous valves
4. Regulation of cardiac output - by controlling venous return to the heart
5. Regulation of arterial pressure - sympathetic venoconstriction shifts blood into the arterial side

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SECTION 8: VENOUS PRESSURES

Central Venous Pressure (CVP) = Right Atrial Pressure

• All systemic veins drain into the right atrium
• Right atrial pressure = central venous pressure (CVP)
• Regulated by balance between:
  1. Heart's pumping ability (stronger pumping → lower RA pressure)
  2. Venous return from peripheral veins (more return → higher RA pressure)

• Range: -2 to +6 mm Hg

1. Increased blood volume
2. Increased venous tone (sympathetic venoconstriction) → peripheral veins constrict → blood shifted centrally
3. Arteriolar dilation → decreased peripheral resistance → blood flows more rapidly from arteries to veins to RA
4. Heart failure (impaired RV pumping)
5. Tricuspid regurgitation
6. Cardiac tamponade

1. Hemorrhage/hypovolemia
2. Increased heart pumping (sympathetic stimulation)
3. Upright posture (blood pools in dependent veins)

Peripheral Venous Pressures

• When standing upright, venous pressure in the foot rises to approximately +90 mm Hg due to the hydrostatic column of blood from the foot to the heart (~1.3 m tall)
• This increased pressure at the foot promotes capillary filtration → edema tendency in lower limbs during prolonged standing

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SECTION 9: THE VENOUS PUMP (MUSCLE PUMP)

Mechanism

1. Peripheral veins have one-way valves (venous valves) that only allow flow toward the heart
2. When skeletal muscles contract → compress the veins in the muscle → pressure rises → blood squeezed toward heart (valves in the other direction closed)
3. When muscles relax → veins refill from capillaries; valves prevent backflow
4. Net effect: continuous forward propulsion of venous blood with muscular activity

Importance of the Venous Pump

• During exercise: Skeletal muscle pump can increase venous return dramatically → supports large increases in cardiac output
• During standing: Without the pump, blood pools in the lower extremities. The pump counteracts hydrostatic pressure and reduces venous/capillary pressure in the feet during walking
• Absence of pump (prolonged standing/immobility):
  • Venous pressure in feet rises markedly (~90 mm Hg)
  • Capillary filtration exceeds lymphatic drainage → edema of ankles and feet

Varicose Veins

• Caused by failure or incompetence of venous valves
• Veins become chronically distended, tortuous, and visible under the skin
• Common in lower extremities (great saphenous vein system)
• Risk factors: prolonged standing, pregnancy (increased abdominal pressure compresses pelvic veins), obesity, hereditary valve weakness
• Consequence: blood pools → increased venous/capillary pressure → edema, skin changes, venous stasis ulcers

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SECTION 10: THE VEINS AS A BLOOD RESERVOIR

Blood Distribution in the Systemic Veins

Spleen as a Special Reservoir

• Stores blood in a highly concentrated form (higher hematocrit than systemic blood)
• During sympathetic stimulation or exercise: splenic capsule contracts → expels high-Hct blood into systemic circulation → increases oxygen-carrying capacity
• More important in animals (dogs can release ~400 mL); in humans the effect is smaller (~100-200 mL)

Clinical Applications of Venous Reservoir Function

• Because venous compliance is so high, transfusing 500 mL into a healthy person changes CVP by only ~3-5 mm Hg → person barely notices
• The veins simply expand to accommodate the extra volume

• Sympathetic activation → venoconstriction → blood mobilized from venous reservoirs → venous return maintained → cardiac output maintained despite blood loss
• First compensatory mechanism for blood loss

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SECTION 11: EFFECT OF GRAVITY AND POSTURE ON VENOUS PRESSURE

Hydrostatic Pressure Effects

• Below the heart: Hydrostatic pressure adds to venous pressure
  • Every 13.6 mm blood column height = 1 mm Hg extra pressure
  • At the foot (~105 cm below heart) → ~+90 mm Hg extra venous pressure
• Above the heart: Hydrostatic pressure subtracts from venous pressure
  • At the top of the head (~30 cm above heart) → venous pressure may be near zero or even slightly negative
  • Jugular veins collapse above the heart level (no venous valves in neck to prevent backflow; maintained open by negative intrathoracic pressure)

Practical Consequences

• Edema formation in ankles during prolonged standing → high local venous and capillary pressure
• Fainting on prolonged standing: blood pools in dependent veins → reduced venous return → reduced CO → reduced cerebral perfusion → syncope
• Postural hypotension: On suddenly standing up, blood pools in lower limbs → transient fall in CO and BP → dizziness (compensated within seconds by baroreceptor reflex)

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SECTION 12: MEASUREMENT OF VENOUS PRESSURE

Direct Measurement (CVP)

• Central venous catheter placed in the jugular vein or subclavian vein with tip at the junction of SVC and RA
• Normal CVP = 2-8 mm Hg (0-6 cm H₂O above the tricuspid valve level)
• Elevated CVP: right heart failure, fluid overload, cardiac tamponade, tension pneumothorax
• Low CVP: hypovolemia, vasodilation

Clinical Estimation (Jugular Venous Pressure - JVP)

• Patient positioned at 45° incline
• Observe the jugular vein for the level of pulsation above the sternal angle (angle of Louis)
• Normal: JVP level ≤ 4 cm above the sternal angle (≈ CVP ≤ 9 cm H₂O)
• Elevated JVP = elevated CVP = right heart failure, fluid overload

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KEY NUMBERS TO REMEMBER - CHAPTER 15

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GUYTON & HALL - TEXTBOOK OF MEDICAL PHYSIOLOGY

CHAPTER 16: The Microcirculation and Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow

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OVERVIEW

• Structure of the capillary system and capillary wall
• How substances exchange across capillary walls
• The Starling forces governing fluid filtration and reabsorption
• The interstitial fluid compartment
• The lymphatic system and its role in fluid balance
• The causes and safety factors against edema

• The body has approximately 10 billion capillaries
• Total capillary surface area: 500-700 m² (~1/8th of a football field)
• No functional cell is more than 20-30 μm from a capillary

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SECTION 1: STRUCTURE OF THE MICROCIRCULATION

The Microvascular Hierarchy

1. Nutrient artery branches 6-8 times → become arterioles
2. Arterioles (internal diameter 10-15 μm): highly muscular; major resistance vessels
3. Arterioles branch 2-5 more times → reach 5-9 μm diameter at terminal arterioles
4. Metarterioles (terminal arterioles): no continuous muscular coat; smooth muscle fibers encircle at intermittent points
5. True capillaries arise from metarterioles; at each origin a precapillary sphincter encircles the entry
6. Capillaries → venules → larger veins

Key Structures at the Microvascular Level

Arterioles

• Highly muscular - can change diameter markedly
• Act as the principal resistance vessels of the circulation
• Controlled by local tissue conditions (metabolic needs), autonomic nerves, and hormones

Metarterioles (Terminal Arterioles)

• No continuous muscular coat
• Smooth muscle fibers at intermittent points only
• In close contact with the tissues they serve
• Respond directly to local tissue conditions (nutrient concentrations, metabolic end products, H⁺ ions)

Precapillary Sphincters

• Single smooth muscle fiber encircling the entrance of each true capillary
• Can open and close the entrance to individual capillaries
• Control how many capillaries are open/perfused at any time
• Regulated by local tissue conditions → intermittent opening and closing = vasomotion

Vasomotion

• Intermittent contraction and relaxation of metarterioles and precapillary sphincters
• Frequency: 6-12 times/min (varies with metabolic needs)
• When O₂ delivery is adequate: sphincters close → capillary not perfused
• When O₂ deficient: sphincters open → capillary opens → O₂ delivered
• At rest: only 20-35% of all capillaries are open at any time
• During maximal exercise in skeletal muscle: virtually 100% open simultaneously

Pericytes

• Found in many capillaries, especially brain and kidneys
• Wrap around endothelial cells at intervals along the capillary wall
• Not smooth muscle cells, but contain contractile proteins
• Secrete factors regulating capillary growth and tissue perfusion
• In the brain: high-density pericytes contribute to the blood-brain barrier (restricts entry of pathogens and large molecules into CNS)

Venules

• Larger than arterioles
• Much weaker muscular coat than arterioles
• Pressure is much lower than arterioles
• Still capable of some constriction (important in edema formation)

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SECTION 2: STRUCTURE OF THE CAPILLARY WALL

Basic Architecture

• Wall = single layer of endothelial cells (unicellular)
• Surrounded on the outside by a thin basement membrane
• Total wall thickness: ~0.5 μm (extremely thin)
• Internal diameter: 4-9 μm (barely large enough for RBCs to squeeze through single-file)

Capillary Pores - Routes of Exchange

• Thin, slitted, curving channels between adjacent endothelial cells
• Width: 6-7 nm (6-7 billionths of a meter)
• These narrow clefts act as the main route for water and small molecule exchange
• Represent only about 1/1000th of the total capillary surface area, yet allow for rapid exchange because they are concentrated along a thin path

• Large numbers of vesicles formed from the cell membrane by endocytosis
• Diameter: 25-70 nm each
• Can coalesce to form transient transcapillary channels from the luminal to the abluminal surface
• Called vesiculo-vacuolar organelles when they fuse into larger channels
• Important route for large molecule transport (including some proteins)
• Rapid vesicular transport: molecules captured on one side, transported across cytoplasm, released on other side

Organ-Specific Capillary Types

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SECTION 3: EXCHANGE OF SUBSTANCES ACROSS THE CAPILLARY WALL

Three Mechanisms of Transcapillary Exchange

• By far the most important mechanism for exchange of nutrients and waste products
• Molecules move from areas of high concentration to low concentration
• Water-soluble substances (glucose, amino acids, ions) diffuse through the intercellular clefts and water-filled channels
• Lipid-soluble substances (O₂, CO₂, fatty acids, steroid hormones, ethanol) diffuse directly through the lipid bilayer of the endothelial cells → much more rapidly than water-soluble substances
• O₂ and CO₂ can diffuse through all parts of the capillary wall because they are highly lipid-soluble

• The total quantity of substance that diffuses = Fick's Law: J = P × A × ΔC
  • J = diffusion rate
  • P = permeability coefficient of the capillary wall for the substance
  • A = surface area available
  • ΔC = concentration difference across the membrane

• Driven by hydrostatic and osmotic pressure differences across the capillary wall (Starling forces - see Section 4)
• Moves water along with its dissolved small molecules
• Quantitatively small relative to diffusion, but critically important for fluid balance

• Plasmalemmal vesicles engulf fluid/solutes from one side → transport across cytoplasm → release other side
• Important for large molecules (albumin, immunoglobulins, insulin) that cannot fit through pores
• Responsible for the small but significant protein leakage from capillaries into the interstitium

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SECTION 4: STARLING FORCES - FILTRATION AND REABSORPTION AT THE CAPILLARY

The Four Starling Forces

The Starling Equation

Net filtration pressure = (Pc + πif) - (Pif + πp) Net filtration pressure = Filtration forces - Reabsorption forces

NFP = (Pc - Pif) - (πp - πif)

• Positive NFP = net filtration (fluid leaves capillary)
• Negative NFP = net reabsorption (fluid enters capillary)

Calculating NFP at Each End of the Capillary

• At the arterial end: fluid filters OUT of capillary into interstitium
• At the venous end: fluid is reabsorbed FROM interstitium BACK into capillary
• Net across the whole capillary: slightly more is filtered out than reabsorbed (net filtration ~2 mm Hg equivalent)
• The excess filtered fluid (~2 L/day) is returned to the circulation via lymphatics

Filtration Coefficient (Kf)

Net fluid filtration rate = Kf × Net filtration pressure

• Kf = hydraulic conductivity × surface area
• Units: mL/min per mm Hg per 100 g tissue
• Varies enormously between organs:
  • Renal glomerulus: very high Kf (designed for massive filtration)
  • Blood-brain barrier: very low Kf (designed to minimize fluid leakage)

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SECTION 5: CAPILLARY HYDROSTATIC PRESSURE IN DETAIL

Values in Different Organs/Conditions

Why Glomerular Pressure is So High

• Afferent arteriole pressure = high (systemic arterial)
• Efferent arteriole provides resistance after the capillary bed
• High pressure maintained throughout glomerular capillary → drives massive filtration (~180 L/day GFR)

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SECTION 6: PLASMA COLLOID OSMOTIC PRESSURE (ONCOTIC PRESSURE)

Definition

• The osmotic pressure exerted by large proteins in the plasma that are too large to cross the capillary membrane freely
• Principal proteins: albumin (~80% of total), globulins, fibrinogen

Normal Values

Gibbs-Donnan Effect

• Plasma proteins carry negative charges at physiological pH
• These negative charges attract cations (Na⁺, K⁺) → hold extra positive ions in plasma
• This adds an extra ~4 mm Hg to the effective oncotic pressure
• Total effective oncotic pressure: ~28 mm Hg (includes this electrostatic effect)

Clinical Significance of Reduced Oncotic Pressure

• Reduced oncotic pressure → less reabsorption at venous end
• More fluid stays in interstitium → edema
• Causes: malnutrition (kwashiorkor, marasmus), liver failure (reduced albumin synthesis), nephrotic syndrome (massive albumin loss in urine), protein-losing enteropathy

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SECTION 7: INTERSTITIAL FLUID - COMPOSITION AND PRESSURE

Interstitial Space Structure

• NOT simply a watery solution between cells
• Consists of two components:
  1. Collagen fiber bundles - provide structural support; resist compression
  2. Proteoglycan filament gel - highly hydrophilic meshwork filling spaces between collagen; traps water

Interstitial Fluid Hydrostatic Pressure (Pif)

• Average: -3 mm Hg (slightly below atmospheric)
• Range by method: -2 to -6 mm Hg

• Lymphatics continuously pump fluid OUT of the interstitium → create a slight suction
• The negative pressure keeps the interstitium "dry" and prevents accumulation of free fluid

• Brain (enclosed by rigid skull): interstitial pressure positive (~10 mm Hg)
• Kidney (enclosed by fibrous capsule): positive (~13 mm Hg)
• Skeletal muscle (fibrous sheaths): slightly positive
• Eye (sclera): slightly positive

Interstitial Fluid Protein Concentration

• Most tissues: ~2 g/dL (much less than plasma's ~7.3 g/dL)
• Liver interstitium: ~6 g/dL (highly fenestrated sinusoidal capillaries)
• Intestinal interstitium: ~3-4 g/dL
• These proteins generate the interstitial colloid osmotic pressure of ~8 mm Hg

The Interstitium Has Free Fluid and Gel-Trapped Fluid

• Most interstitial fluid is trapped in the proteoglycan gel matrix and is not freely mobile
• Only when the interstitium becomes overfilled does free fluid appear → this free fluid then causes pitting edema
• The gel-trapped water resists the formation of large pools of free fluid (provides a safety buffer)

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SECTION 8: EDEMA - CAUSES, TYPES, AND SAFETY FACTORS

Definition

Causes of Edema

• Venous obstruction (thrombosis, tumor)
• Heart failure (right-sided → peripheral edema; left-sided → pulmonary edema)
• Excessive blood volume (renal retention of Na⁺ and water)
• Dependent edema from gravity (prolonged standing)

• Severe malnutrition → low albumin → low oncotic pressure → edema
• Liver failure → reduced albumin synthesis → edema (especially ascites)
• Nephrotic syndrome → massive albuminuria → low plasma albumin → generalized edema
• Protein-losing enteropathy

• Allergic reactions (histamine → markedly increases permeability → angioedema, urticaria)
• Burns → destroy capillary walls → massive protein leakage → enormous edema
• Bacterial toxins (gram-negative endotoxins)
• Inflammatory mediators (bradykinin, prostaglandins, leukotrienes, IL-1, TNF-α)
• ARDS (acute respiratory distress syndrome) → pulmonary edema from capillary leak

• Obstruction prevents return of leaked proteins from interstitium
• Proteins accumulate → increase interstitial oncotic pressure → more fluid pulled out → edema
• Also: lymph cannot drain → fluid accumulates
• Causes: filariasis (Wuchereria bancrofti → elephantiasis), cancer invading lymph nodes, surgical removal of lymph nodes (e.g., mastectomy → arm edema), radiation therapy

Three Safety Factors Against Edema

• Normal interstitial fluid pressure: -3 mm Hg
• The proteoglycan gel matrix resists expansion at low pressures
• As filtration pressure increases, interstitial fluid pressure rises only a little (from -3 toward 0 mm Hg)
• Safety factor: +3 mm Hg (the rise from -3 to 0 mm Hg opposes further filtration)

• As interstitial pressure rises → lymphatic drainage dramatically increases (up to 20-fold when Pif rises from -6 to 0 mm Hg)
• Lymphatics can remove the extra filtered fluid before it accumulates
• Safety factor: ~7 mm Hg (lymph flow can compensate for increased filtration equivalent to ~7 mm Hg rise in filtration pressure)

• As more fluid filters into the interstitium → interstitial proteins are diluted (washed out)
• Interstitial protein concentration falls → interstitial oncotic pressure (πif) falls
• Falling πif → less force pulling fluid OUT → reduced net filtration
• Safety factor: ~7 mm Hg (can accommodate an equivalent 7 mm Hg increase in filtration pressure)

• Capillary pressure can rise from its normal ~17 mm Hg to ~34-35 mm Hg before edema appears
• Or: plasma oncotic pressure can fall to ~11 mm Hg before edema appears

Edema Formation Sequence After Safety Factors Are Overwhelmed

1. Capillary filtration exceeds reabsorption + lymphatic drainage
2. Interstitial fluid volume increases
3. Interstitial pressure rises to 0 mm Hg and above (becomes positive)
4. Free fluid appears in the interstitium (no longer gel-trapped)
5. Pitting edema becomes clinically detectable

Pulmonary Edema - Special Considerations

• Pulmonary capillary pressure normally ~7 mm Hg (very low, below oncotic pressure)
• Pulmonary interstitial fluid pressure: -8 mm Hg (very negative due to expansile forces of lung tissue)
• When left heart fails → pulmonary capillary pressure rises
• If pulmonary capillary pressure rises above ~30 mm Hg → outstrips pulmonary oncotic pressure → acute pulmonary edema
• Fluid fills alveoli → impairs gas exchange → can be fatal

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SECTION 9: THE LYMPHATIC SYSTEM

Overview of Lymphatic Function

1. Returns excess interstitial fluid (and proteins) to the circulation
2. Removes proteins that continuously leak from blood capillaries (critical - proteins cannot return via blood capillary reabsorption)
3. Transports absorbed fats from the intestinal lacteals to the circulation

Structure of Lymphatic Capillaries

• Terminal lymphatic capillaries: blind-ended, highly permeable tubes in the interstitium
• Endothelial cells attached to surrounding connective tissue by anchoring filaments
• Adjacent endothelial cells overlap at their edges → form flap valves
  • When tissue swells: anchoring filaments pull open flap valves → interstitial fluid (with proteins and particles) enters lymphatic
  • When tissue is compressed: valves close → fluid propelled forward (not backward)
• One-way valves at every level of the lymphatic system prevent backflow

Formation and Composition of Lymph

• Lymph = interstitial fluid that has entered the lymphatic capillaries
• Composition closely mirrors interstitial fluid
• Protein concentration in lymph from different tissues:
  • Most tissues: ~2 g/dL
  • Liver lymph: up to 6 g/dL (liver capillaries are very leaky to proteins)
  • Intestinal lymph: 3-4 g/dL
  • Thoracic duct (mixed lymph): 3-5 g/dL (2/3 of all lymph comes from liver and intestines)

• Fats: After a fatty meal, lymph in the thoracic duct contains 1-2% fat (chylomicrons absorbed from intestinal lacteals via chyle)
• Bacteria: Large particles including bacteria can push through lymphatic endothelial junctions → enter lymph → filtered out and destroyed in lymph nodes

Lymph Flow Rate

• Total lymph flow: ~100 mL/hr through the thoracic duct + ~20 mL/hr through other channels
• Total: ~120 mL/hr = ~3 L/day returned to circulation via lymphatics
• This equals the approximate excess filtration from blood capillaries

Factors Increasing Lymph Flow

1. Increased capillary hydrostatic pressure → more filtration → more interstitial fluid → higher Pif → more lymph flow
2. Decreased plasma oncotic pressure
3. Increased capillary permeability
4. Increased interstitial oncotic pressure

• At normal Pif (-6 mm Hg): lymph flow is very low (nearly zero)
• As Pif rises from -6 to 0 mm Hg: lymph flow increases more than 20-fold
• Maximum lymph flow is reached when Pif reaches ~0 mm Hg

The Lymphatic Pump - How Lymph Moves

• Walls of larger lymphatic vessels (>1 mm diameter) contain smooth muscle
• Smooth muscle contracts rhythmically (~6-10 times/min) when distended by lymph
• Each lymphangion (segment between valves) contracts sequentially → propels lymph forward
• Analogous to the peristalsis in the intestine

• Skeletal muscle contractions (most important)
• Arterial pulsations (adjacent arteries compress lymphatics)
• Body movements
• Respiratory movements (changes in intrathoracic pressure)
• Tissue compression by external objects

Lymphatic Capillary Pump

• Anchoring filaments pull capillary walls open when tissue swells → fluid enters
• When tissue compressed → overlapping endothelial flap valves close → fluid propelled forward
• Endothelial cells themselves contain some actomyosin filaments → can rhythmically contract

Determinants of Lymph Flow Rate

• High Pif with blocked/absent lymphatics → edema (lymphedema)
• Active pump with low Pif → minimal flow (little fluid to move)

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SECTION 10: LYMPHATIC SYSTEM CONTROL OF INTERSTITIAL FLUID HOMEOSTASIS

1. Interstitial Fluid Protein Concentration

• Blood capillaries continuously leak small amounts of protein
• These proteins cannot return via the venous end of capillaries (too large)
• Without lymphatics: proteins would accumulate → increasing πif → pulling more fluid out → progressive edema
• Lymphatics drain these proteins → return to blood → maintain low interstitial protein concentration

2. Interstitial Fluid Volume

• Lymphatics act as the overflow mechanism when filtration exceeds reabsorption
• Continuous drainage prevents accumulation of excess fluid

3. Interstitial Fluid Pressure

• By removing fluid, lymphatics maintain the slightly negative Pif (-3 mm Hg)
• This negative pressure keeps the interstitium "collapsed" around cells → prevents free fluid lakes from forming

The Homeostatic Equilibrium (Self-Regulating System)

1. Proteins leak from capillaries → accumulate in interstitium → πif rises
2. Rising πif → more fluid filtered out → interstitial volume ↑ → Pif rises
3. Rising Pif → lymph flow dramatically increases
4. Increased lymph flow → carries proteins AND fluid back to blood
5. πif and Pif return toward normal

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KEY NUMBERS TO REMEMBER - CHAPTER 16

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The One Rule You Need

A lead records POSITIVE if the mean electrical axis points TOWARD its positive electrode. Negative if it points AWAY.

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Step 1 - Know Where Each Lead's Positive Electrode Points

        aVL (-30°)
           |
Lead I (0°) ←————————
           |
        aVF (+90°)

Lead II = +60°
Lead III = +120°
aVR = -150°

• Lead I = pointing LEFT (0°)
• Lead II = pointing LEFT-DOWN (60°)
• Lead III = pointing RIGHT-DOWN (120°)
• aVF = pointing straight DOWN (90°)
• aVL = pointing LEFT-UP (-30°)
• aVR = pointing RIGHT-UP (-150°) → always opposite to most leads

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Step 2 - The Angle Test (No Drawing Needed)

"Is the axis pointing MORE toward or MORE away from this lead's positive pole?"

• Less than 90° → axis is in the same "half" as the positive pole → POSITIVE deflection
• More than 90° → axis is in the opposite "half" → NEGATIVE deflection
• Exactly 90° → axis is perpendicular to the lead → isoelectric (flat/biphasic)

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Your Example: Axis in the Left Upper Quadrant (~-60°)

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The Even Simpler Visual Trick

• Imagine the lead as a LINE through the center (positive end and negative end)
• Ask: which side of the line does the arrow point toward?
• Arrow points toward positive side = positive QRS
• Arrow points toward negative side = negative QRS
• Arrow lies exactly on the line = isoelectric

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Quick Memory Aid for Common Axes

• If Lead I and aVF are both positive → Normal axis ✓
• If Lead I positive, aVF negative → Left axis deviation
• If Lead I negative, aVF positive → Right axis deviation
• If both negative → Extreme axis deviation (northwest)

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What You Are Actually Doing

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The Setup - Draw This Once and Memorize It

        RA ————————————— LA
         \               /
          \             /
           \           /
            \         /
             \       /
              \     /
               \   /
                \ /
                 LL

                    -90°
                     |
         aVL        |        
        (-30°)  \   |   /  
                 \  |  /   
    Lead I ———————CENTER——————— Lead I
    (0°, left)   /  |  \      (180°, right)
                /   |   \
               /    |    \
          Lead II  aVF   Lead III
          (+60°)  (+90°) (+120°)
                     |
                   +90°

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The Step-by-Step Method

Step 1: Measure net QRS voltage in Lead I

• Add up all upward deflections (positive)
• Subtract all downward deflections (negative)
• Result = net voltage of Lead I (can be + or -)

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Step 2: Measure net QRS voltage in Lead III

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Step 3: Plot Lead I on its axis

• Draw the Lead I axis = horizontal line through center
• Positive end is to the LEFT (0°), negative end is to the RIGHT (180°)
• Mark a point +6 mm to the LEFT of center along this line
• Label this point A

    ← positive          negative →
    |___A___|___center___|_________|
         +6mm

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Step 4: Plot Lead III on its axis

• Draw the Lead III axis = line at +120° through center (going lower-right)
• Mark a point +3 mm along the positive direction (+120° direction) from center
• Label this point B

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Step 5: Draw perpendicular lines from A and B

• From point A (on the Lead I axis): draw a line perpendicular to the Lead I axis
  • Lead I is horizontal → its perpendicular is vertical
  • So draw a vertical line upward AND downward through point A
• From point B (on the Lead III axis): draw a line perpendicular to the Lead III axis
  • Lead III is at 120° → its perpendicular is at 120° - 90° = 30°
  • So draw a line at 30° through point B

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Step 6: Mark where the two perpendicular lines intersect

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Step 7: Draw the mean axis vector

• Draw an arrow from the CENTER of the diagram to point C
• This arrow IS the mean electrical axis
• Measure the angle of this arrow from the horizontal → that angle is your mean QRS axis in degrees

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Visual Walkthrough With Numbers

STEP 1-2: Net voltages
Lead I  = +6 mm
Lead III = +3 mm

STEP 3: Plot on Lead I axis (horizontal)
         Mark +6 mm to the LEFT of center → point A

STEP 4: Plot on Lead III axis (lower-right diagonal, 120°)
         Mark +3 mm along the 120° direction → point B

STEP 5: Draw perpendiculars
         From A: draw a VERTICAL line (perpendicular to horizontal Lead I)
         From B: draw a line at 30° (perpendicular to the 120° Lead III axis)

STEP 6: Where these two lines cross = point C

STEP 7: Arrow from center → C = MEAN AXIS
         Measure its angle → ~+59° (normal axis)

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Why This Works (The Logic)

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The One Thing That Confuses Everyone

You draw the perpendicular FROM the plotted point, and it must be perpendicular TO that lead's axis.

• Perpendicular from Lead I point = vertical line
• Perpendicular from aVF point = horizontal line
• They cross at a right angle immediately → super easy to find the intersection

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Quick Summary in 3 Lines

1. Measure net QRS in two leads → plot each value along its lead's axis
2. From each plotted point, draw a line perpendicular to that lead's axis
3. Where the two perpendiculars cross → draw arrow from center to that point = mean electrical axis