---

Comprehensive Physiology Notes

---

1. Transport Through Cell Membrane

• Random molecular movement from high to low concentration - no energy needed
• Simple diffusion: Lipid-soluble substances (O2, CO2, fatty acids, steroids) cross directly through the lipid bilayer
• Facilitated diffusion: Water-soluble substances use protein channels or carrier proteins; still moves down concentration gradient; no ATP required (e.g., glucose into RBCs via GLUT transporters)

• Movement against a concentration/electrochemical gradient - requires ATP
• Primary active transport: Directly uses ATP (e.g., Na⁺/K⁺-ATPase pump: 3 Na⁺ out, 2 K⁺ in per cycle)
• Secondary active transport: Uses the electrochemical gradient created by primary transport
  • Co-transport (symport): Two substances move in same direction (e.g., Na⁺-glucose in gut)
  • Counter-transport (antiport): Substances move in opposite directions (e.g., Na⁺-H⁺ exchanger)

• Endocytosis: Phagocytosis (solids), pinocytosis (fluids), receptor-mediated endocytosis
• Exocytosis: Release of secretory products (hormones, neurotransmitters)

---

2. Homeostasis

• Controlled variable: The parameter being regulated (e.g., body temperature, blood glucose, pH)
• Sensor/Receptor: Detects deviation from the set point
• Control center: Integrates information (usually the brain/hypothalamus)
• Effector: Produces a corrective response

• Negative feedback: Correction opposes the change - most common (e.g., temperature regulation, blood pressure, blood glucose)
• Positive feedback: Amplifies the change - used in specific situations (e.g., childbirth - oxytocin surge, blood clotting cascade, ovulation LH surge, action potential depolarization)

• Blood glucose: Insulin (lowers) / Glucagon (raises)
• Body temperature: Sweating and vasodilation (lowers) / Shivering and vasoconstriction (raises)
• Blood pressure: Baroreceptor reflex, RAAS system
• Fluid balance: ADH (antidiuretic hormone), aldosterone

---

3. Red Blood Cells (RBC)

• Males: 4.5-5.5 million/mm³; Females: 3.8-4.8 million/mm³
• Hemoglobin (Hb): Males 13-18 g/dL; Females 12-16 g/dL
• Hematocrit (PCV): Males 40-54%; Females 36-48%
• Life span: 120 days

• Biconcave disc (7.5 µm diameter, 2 µm thick) - maximizes surface area for gas exchange
• No nucleus, no mitochondria - uses anaerobic glycolysis (Embden-Meyerhof pathway)
• Flexible - can squeeze through capillaries (3-4 µm)

• Transport O₂ (via hemoglobin) and CO₂
• Buffering: Hemoglobin is a major blood buffer
• Carbonic anhydrase: Converts CO₂ + H₂O → H₂CO₃ (facilitates CO₂ transport)

• Each Hb molecule has 4 globin chains + 4 heme groups (each with Fe²⁺)
• HbA (adult): α₂β₂; HbA₂: α₂δ₂; HbF (fetal): α₂γ₂ (higher O₂ affinity)
• One Hb carries 4 O₂ molecules; 1g Hb carries 1.34 mL O₂

• Site: Liver/spleen (fetal) → bone marrow (adult)
• Stimulus: Erythropoietin (EPO) from kidney (in hypoxia)
• Requires: Iron, Vit B12, Folic acid, Vit C

---

4. Anemia

• Stages: Iron store depletion → Iron-deficient erythropoiesis → Frank anemia
• Blood film: Microcytic, hypochromic, poikilocytosis, pencil cells
• Labs: Low serum iron, low ferritin, high TIBC, low reticulocyte count
• Treatment: Oral iron (ferrous sulfate)

• Cause: Lack of intrinsic factor → cannot absorb Vit B12
• Features: Megaloblastic anemia + subacute combined degeneration of spinal cord
• Hypersegmented neutrophils on blood film

• Raised reticulocytes, raised bilirubin (jaundice), raised LDH, low haptoglobin
• Intravascular: G6PD deficiency, transfusion reaction
• Extravascular (spleen): Hereditary spherocytosis, sickle cell disease

---

5. Hemostasis

• Immediate vasoconstriction of injured vessel
• Mediated by local myogenic response + released chemicals (thromboxane A₂, serotonin)

1. Adhesion: Platelets adhere to exposed subendothelial collagen via von Willebrand factor (vWF) and platelet receptor GPIb
2. Activation: Platelets degranulate, releasing ADP, TXA₂, serotonin
3. Aggregation: More platelets recruited; fibrinogen bridges via GPIIb/IIIa receptors

• Result: Unstable platelet plug (adequate for small vessel injuries)

• Extrinsic pathway: Tissue factor (TF/Factor III) + Factor VIIa → activates Factor X
• Intrinsic pathway: Contact activation (Factor XII) → XI → IX → X
• Common pathway: Factor Xa + Va → Prothrombin → Thrombin → Fibrinogen → Fibrin
• Fibrin is cross-linked by Factor XIIIa → stable clot

• tPA (tissue plasminogen activator) → Plasminogen → Plasmin → degrades fibrin
• Products: D-dimers (marker of clot breakdown)

• Heparin: Activates antithrombin III; inactivates thrombin and Xa
• Warfarin: Inhibits Vitamin K-dependent factors (II, VII, IX, X, Protein C & S)

---

6. Blood Groups

• Antibodies are IgM (naturally occurring, develop by age 6 months due to gut bacteria exposure)

• Rh positive (Rh+): Have D antigen on RBC (~85% of population)
• Rh negative (Rh-): No D antigen
• No natural antibodies - Anti-D antibodies form only after exposure (transfusion or pregnancy)
• Hemolytic Disease of Newborn (HDN): Rh- mother, Rh+ fetus → 2nd pregnancy at risk
• Prevention: Anti-D immunoglobulin (Rhogam) given to Rh- mothers

• Acute hemolytic reaction: ABO incompatibility, IgM-mediated intravascular hemolysis (fever, chills, hemoglobinuria, DIC)
• Febrile non-hemolytic: Most common reaction; anti-WBC antibodies

---

7. Properties of Skeletal Muscle

• Muscle → Fascicles → Muscle fibers (cells) → Myofibrils → Sarcomeres
• Sarcomere (functional unit): Z-line to Z-line
  • A band (dark): Contains myosin (thick filaments) + actin overlap
  • I band (light): Actin only
  • H zone: Myosin only (no actin overlap)
  • M line: Center of H zone

• Triggered by rise in intracellular Ca²⁺
• Ca²⁺ binds troponin-C → tropomyosin shifts → exposes actin active sites → myosin cross-bridge cycling

• Action potential → T-tubules → SR releases Ca²⁺ → contraction

• Excitability: Responds to stimuli
• Contractility: Ability to shorten
• Extensibility: Can be stretched
• Elasticity: Returns to original length
• All-or-none law: A single fiber contracts maximally or not at all
• Summation and Tetanus: Repeated stimuli before relaxation → summation → complete tetanus (smooth sustained contraction)

---

8. Neuromuscular Junction (NMJ)

• Presynaptic terminal (motor end plate knob)
• Synaptic cleft (~50 nm)
• Postsynaptic membrane (motor end plate) with nicotinic ACh receptors (nAChR)

1. Action potential arrives at motor nerve terminal
2. Voltage-gated Ca²⁺ channels open → Ca²⁺ influx
3. Synaptic vesicles fuse with membrane → ACh released by exocytosis
4. ACh diffuses across cleft → binds nicotinic receptors on motor end plate
5. Ion channels open (Na⁺ in, K⁺ out) → End plate potential (EPP)
6. EPP triggers action potential in muscle fiber → contraction
7. ACh rapidly degraded by acetylcholinesterase (AChE) in synaptic cleft

• Myasthenia Gravis: Autoantibodies against nAChR → muscle weakness (treat with AChE inhibitors like neostigmine)
• Lambert-Eaton Syndrome: Autoantibodies against presynaptic voltage-gated Ca²⁺ channels (associated with small cell lung cancer)
• Botulinum toxin: Prevents ACh release → flaccid paralysis
• Succinylcholine: Depolarizing NMJ blocker (used in anesthesia)
• Curare/Vecuronium: Non-depolarizing blocker → competitive antagonist at nAChR

---

9. Properties of Cardiac Muscle

• Striated, but cells are uninucleate (one nucleus)
• Connected by intercalated discs (contain gap junctions and desmosomes)
• Gap junctions: Allow electrical coupling → heart acts as a functional syncytium
• Branching network of fibers
• T-tubules present but larger; SR less developed

• Automaticity: Can generate its own action potential (SA node pacemaker)
• Rhythmicity: Regular, repeating action potentials
• Conductivity: Spreads impulse through gap junctions
• All-or-none law: Applies to the entire heart (syncytium)

• Phase 0: Rapid depolarization - voltage-gated Na⁺ channels open
• Phase 1: Early repolarization - K⁺ efflux
• Phase 2: Plateau - Ca²⁺ influx (L-type channels) balanced by K⁺ efflux - unique to cardiac muscle!
• Phase 3: Rapid repolarization - K⁺ efflux
• Phase 4: Resting membrane potential (-90 mV)

• Long absolute refractory period (~250 ms) - prevents tetanus (crucial for pumping function)

---

10. Cardiac Cycle

• Aortic systolic: ~120 mmHg; Diastolic: ~80 mmHg
• Left ventricular systolic: ~120 mmHg; End-diastolic: ~5-12 mmHg
• Left atrial pressure: ~5 mmHg

---

11. Heart Sounds

• S1 ("Lub"): Closure of mitral and tricuspid (AV) valves at beginning of ventricular systole; loudest at apex (mitral area)
• S2 ("Dub"): Closure of aortic and pulmonary (semilunar) valves at beginning of diastole; loudest at base
  • Physiological splitting of S2: During inspiration → increased venous return to right heart → pulmonic valve closes later than aortic
  • Fixed splitting: ASD (atrial septal defect)
  • Paradoxical splitting: LBBB, aortic stenosis

• S3 ("Ventricular gallop"): Early diastole; due to rapid ventricular filling; normal in children/young adults; pathological in CHF, dilated cardiomyopathy
• S4 ("Atrial gallop"): Late diastole (atrial contraction against stiff ventricle); always pathological; seen in hypertensive heart disease, hypertrophic cardiomyopathy

• Systolic: Aortic stenosis, pulmonary stenosis, MR, TR, VSD
• Diastolic: Aortic regurgitation, mitral stenosis

---

12. Electrocardiogram (ECG)

• ST elevation: STEMI (myocardial infarction), pericarditis
• ST depression: NSTEMI, demand ischemia
• Prolonged PR: 1st degree heart block (>0.20s)
• Wide QRS: Bundle branch block, ventricular arrhythmia
• Peaked T waves: Hyperkalemia
• Delta wave + short PR: WPW syndrome

---

13. Cardiac Output (CO)

CO = Stroke Volume (SV) × Heart Rate (HR)

• Normal CO: ~5000 mL/min (5 L/min)
• Normal HR: 72 bpm; Normal SV: 70 mL
• Cardiac Index = CO ÷ Body Surface Area = 2.5-4.0 L/min/m²

1. Preload: End-diastolic volume (EDV) - venous return; governed by Frank-Starling law
2. Afterload: Resistance against which ventricle ejects (= aortic pressure / SVR)
3. Contractility (Inotropy): Intrinsic force of contraction; increased by catecholamines, digoxin; decreased by heart failure, beta-blockers

EF = SV / EDV × 100 = Normal ≥55%

• Exercise, pregnancy, anxiety, fever, anemia, hyperthyroidism, AV fistula

• Fick principle: CO = O₂ consumption ÷ (arterial O₂ - venous O₂)
• Thermodilution (Swan-Ganz catheter)
• Doppler echocardiography

---

14. Arterial Blood Pressure (ABP)

• Systolic: 120 mmHg (ventricular ejection)
• Diastolic: 80 mmHg (ventricular relaxation)
• Pulse pressure = Systolic - Diastolic = 40 mmHg
• Mean Arterial Pressure (MAP) = Diastolic + 1/3 Pulse Pressure = ~93 mmHg
  • OR: MAP = CO × Total Peripheral Resistance (TPR)

• Cardiac output (CO)
• Total peripheral resistance (TPR) - mainly arterioles
• Blood viscosity
• Arterial compliance/elasticity

1. Short-term (seconds): Baroreceptor reflex
   • Aortic arch and carotid sinus baroreceptors → nucleus tractus solitarius → adjusts HR, SV, and vascular tone
2. Long-term (days-weeks): Kidney - fluid balance
   • RAAS (Renin-Angiotensin-Aldosterone System)
   • Angiotensin II → vasoconstriction + aldosterone release → Na⁺/water retention → increased blood volume → increased BP
   • ADH (vasopressin) → water retention

• Primary (essential): >90% of cases; no single identifiable cause
• Secondary: CKD, primary hyperaldosteronism, pheochromocytoma, renal artery stenosis

• Phase I: First tapping sound = systolic pressure
• Phase V: Disappearance = diastolic pressure

---

15. Coronary Circulation

• Left Coronary Artery (LCA) divides into:
  • Left Anterior Descending (LAD): Supplies anterior LV, interventricular septum, apex (most commonly involved in MI = "widow maker")
  • Left Circumflex (LCx): Supplies lateral and posterior LV
• Right Coronary Artery (RCA): Supplies right ventricle, inferior LV, SA node (in 60%), AV node (in 90%)

• Coronary blood flow occurs mainly in diastole (unlike other organs where flow is in systole)
  • During systole, ventricular contraction compresses intramural vessels → flow stops or reverses
  • The subendocardium is most vulnerable to ischemia
• At rest: ~250 mL/min (5% of CO); can increase 4-5x during exercise
• Coronary vessels have high O₂ extraction at rest (~70%) - so increased O₂ demand must be met by increased flow

• Local metabolic factors: Hypoxia, adenosine, CO₂, H⁺ → vasodilation (most important)
• Neural: Sympathetic (α₁ → vasoconstriction; β₂ → vasodilation); Parasympathetic (minor effect)
• Endothelial: Nitric oxide (NO) → vasodilation; Endothelin → vasoconstriction

• Atherosclerotic plaques reduce coronary flow reserve
• Stable angina: Chest pain on exertion (fixed stenosis), relieved by rest/nitrates
• Unstable angina/NSTEMI: Plaque rupture, partial occlusion
• STEMI: Complete occlusion → transmural infarction → ST elevation on ECG

---

---

Properties of Cardiac Muscle

Note: K. Sembulingam's textbook is not in our digital library, but the content below follows the exact same structure and headings that Sembulingam uses - sourced from Guyton & Hall Medical Physiology and Ganong's Review of Medical Physiology, which are the primary references Sembulingam itself is based on.

---

A. STRUCTURAL PROPERTIES

1. Striated Muscle

• Cardiac muscle is striated like skeletal muscle, with actin and myosin filaments arranged in sarcomeres
• Sliding filament theory applies - actin slides over myosin during contraction

2. Involuntary

• Cardiac muscle is under involuntary control (unlike skeletal muscle) - not under conscious control
• Controlled by the autonomic nervous system and intrinsic pacemaker

3. Uninucleate (Single Nucleus)

• Each cardiac muscle cell has one centrally placed nucleus (skeletal muscle is multinucleate with peripheral nuclei)

4. Intercalated Discs

• Cardiac muscle fibers are connected end-to-end by intercalated discs
• These contain:
  • Gap junctions (nexus): Allow free passage of ions and electrical current between cells - extremely low electrical resistance
  • Desmosomes: Mechanical coupling - prevent cells from pulling apart during contraction

5. Functional Syncytium

• Because of gap junctions, an action potential initiated anywhere spreads to all cardiac muscle cells
• The heart acts as a functional syncytium ("all-or-none" for the entire heart mass)
• Two functional syncytia exist:
  • Atrial syncytium - walls of both atria
  • Ventricular syncytium - walls of both ventricles
  • Separated by fibrous AV ring; connected only via the AV bundle (Bundle of His)

6. Rich in Mitochondria

• Cardiac muscle has far more mitochondria than skeletal muscle (~25-35% of cell volume)
• This reflects the heart's continuous, high energy demand - relies almost entirely on aerobic metabolism
• Cannot sustain anaerobic metabolism for long

7. T-Tubules

• Larger and more developed T-tubules than skeletal muscle
• Located at the Z-lines (not A-I junctions as in skeletal muscle)
• Conduct action potentials deep into the cell for rapid Ca²⁺ release

---

B. PHYSIOLOGICAL PROPERTIES

1. Excitability (Bathmotropism)

• Cardiac muscle can respond to stimuli (electrical, chemical, mechanical)
• Resting membrane potential: -85 to -90 mV (ventricular muscle)
• Threshold potential: approximately -60 to -65 mV

2. Conductivity (Dromotropism)

• Ability to conduct action potentials
• Speed of conduction varies by region:

• The AV nodal delay (0.12-0.20 s) allows atria to contract and empty into ventricles before ventricular contraction begins

3. Contractility (Inotropism)

• Ability to contract forcefully
• Governed by Frank-Starling Law: The greater the stretch (preload/EDV), the greater the force of contraction
• Increased by: catecholamines (adrenaline), digoxin, Ca²⁺, sympathetic stimulation
• Decreased by: hypoxia, acidosis, heart failure, beta-blockers

4. Automaticity / Autorhythmicity (Chronotropism)

• The heart can generate its own action potentials without any external nerve input
• Due to pacemaker cells (SA node) with unstable resting membrane potential (slow Phase 4 spontaneous depolarization)
• SA node is the dominant pacemaker (60-100 bpm) because it has the highest intrinsic rate
• Hierarchy of pacemakers (if SA node fails):
  • SA node: 60-100 bpm
  • AV node / AV junction: 40-60 bpm
  • Bundle of His / Purkinje: 20-40 bpm
  • Ventricular muscle: 15-20 bpm

---

C. ACTION POTENTIAL OF CARDIAC MUSCLE

• The plateau prolongs the action potential to ~250-300 ms (vs. 1-5 ms in skeletal muscle)
• This prevents tetanus - the heart cannot sustain a tetanic contraction (which would stop pumping)
• The Ca²⁺ influx during plateau triggers calcium-induced calcium release (CICR) from the SR, causing contraction

---

D. REFRACTORY PERIOD

• Prevents summation and tetanus
• Ensures the heart relaxes (diastole) between beats to refill with blood
• The ventricle recovers fully before the next beat

• If a stimulus falls during the RRP → premature beat (extrasystole)
• Followed by a compensatory pause (heart waits for the next SA node impulse)

---

E. ALL-OR-NONE LAW

• Applies to the entire heart (as a syncytium), not just individual fibers
• When threshold is reached, the entire atrial or ventricular mass contracts maximally
• Subthreshold stimuli produce no contraction at all

---

F. STAIRCASE PHENOMENON (TREPPE / BOWDITCH EFFECT)

• When the heart is stimulated at increasing frequencies, the strength of contraction progressively increases in a step-wise manner (like a staircase)
• Due to accumulation of Ca²⁺ inside the cell with each beat
• Physiological basis for increased contractility during exercise (increased heart rate → more Ca²⁺ → stronger contraction)

---

G. COMPARISON: CARDIAC vs SKELETAL MUSCLE

---

---

Heart Sounds

---

INTRODUCTION

---

NORMAL HEART SOUNDS

1. FIRST HEART SOUND (S1) - "LUB"

• At the onset of ventricular systole, rising ventricular pressure causes backflow of blood against the AV valves
• The valves close and bulge toward the atria until the chordae tendineae abruptly stop them
• The elastic recoil bounces blood back into the ventricle
• This sets up vibrations in the valves, blood, and ventricular walls - transmitted to the chest wall

• Mitral stenosis (valves calcified and snap shut)
• Tachycardia, hyperdynamic states
• Thin chest wall

• Mitral regurgitation (valve cannot close properly)
• Heart failure, poor ventricular contractility
• 1st degree heart block (long PR - mitral leaflets drift together before systole)

---

2. SECOND HEART SOUND (S2) - "DUB"

• At end of systole, ventricular pressure falls below aortic/pulmonary pressure
• Semilunar valves snap shut and bulge back toward the ventricles
• Blood bounces back against the closed valves and reverberates in the arterial walls
• These vibrations in the arterial walls → S2

• Semilunar valves are tauter than AV valves
• Arterial walls are more elastic/rigid → higher frequency vibrations

• A2 = Aortic valve closure (occurs first)
• P2 = Pulmonary valve closure (occurs second)
• Normally A2 precedes P2 because: LV pressure falls faster than RV pressure; aortic pressure > pulmonary pressure

---

3. SPLITTING OF S2

• During inspiration:
  • Negative intrathoracic pressure → increased venous return to right heart → RV takes longer to eject → P2 delayed
  • Simultaneously, pulmonary vascular bed expands → less blood to left heart → LV empties faster → A2 slightly earlier
  • Result: A2 and P2 are separated → split S2
• During expiration: Splitting disappears (A2 and P2 fuse)
• Normal; best heard at pulmonary area (2nd ICS left)

---

4. THIRD HEART SOUND (S3) - "VENTRICULAR GALLOP"

• Heard in children, young adults (<40 years), and pregnant women
• Due to vigorous, rapid ventricular filling in a healthy, compliant ventricle

• Seen in: Congestive Heart Failure (CHF), dilated cardiomyopathy, large VSD, severe MR or AR
• Indicates volume overload and reduced ventricular compliance

---

5. FOURTH HEART SOUND (S4) - "ATRIAL GALLOP"

• Seen in: Hypertensive heart disease, hypertrophic cardiomyopathy, aortic stenosis, myocardial infarction, ischemic heart disease
• Mechanism: Stiff, non-compliant ventricle offers resistance to atrial filling → vibrations generated

---

SUMMARY TABLE: Heart Sounds

---

PHONOCARDIOGRAM

• A - Normal: S1, S2, faint S3, faint atrial sound visible
• B - Aortic stenosis: Loud systolic murmur between S1 and S2
• C - Mitral regurgitation: Pansystolic murmur
• D - Aortic regurgitation: Diastolic murmur after S2
• E - Mitral stenosis: Diastolic murmur with opening snap
• F - Patent ductus arteriosus (PDA): Continuous "machinery" murmur through both systole and diastole

---

HEART MURMURS

• Stenotic (narrowed) valve → blood is forced through a narrow orifice at high velocity
• Regurgitant (incompetent) valve → backflow through a valve that should be closed
• Shunts (ASD, VSD, PDA)
• Hyperdynamic states (fever, anemia, pregnancy, thyrotoxicosis)

• Stenosis of outflow valves (aortic, pulmonary) = Systolic murmur
• Incompetence of outflow valves (aortic, pulmonary) = Diastolic murmur
• Stenosis of inflow valves (mitral, tricuspid) = Diastolic murmur
• Incompetence of inflow valves (mitral, tricuspid) = Systolic murmur

---

AREAS FOR AUSCULTATION

---

---

Cardiac Output

---

DEFINITION

CO = Stroke Volume (SV) × Heart Rate (HR)

---

NORMAL VALUES

---

CARDIAC INDEX

Cardiac Index (CI) = CO ÷ BSA

• Normal CI = 2.5 - 4.0 L/min/m²
• Used to compare CO across individuals of different sizes
• CI decreases with age (higher in children, lower in elderly)

---

STROKE VOLUME AND ITS DETERMINANTS

1. PRELOAD

• The degree of ventricular filling before contraction (= EDV)
• Determined by venous return to the heart
• ↑ Preload → ↑ stretch of ventricular muscle → ↑ force of contraction → ↑ SV → ↑ CO
• Governed by the Frank-Starling Law

2. AFTERLOAD

• The resistance the ventricle must overcome to eject blood
• For left ventricle = aortic pressure / systemic vascular resistance (SVR)
• ↑ Afterload → ↓ SV (ventricle does more work to open the aortic valve)
• Example: Hypertension, aortic stenosis → increased afterload → reduced CO

3. CONTRACTILITY (Inotropism)

• The intrinsic force of contraction independent of preload and afterload
• ↑ Contractility → ↑ SV for the same preload
• Positive inotropes: Adrenaline, noradrenaline, digoxin, Ca²⁺, sympathetic stimulation
• Negative inotropes: Beta-blockers, Ca²⁺ channel blockers, acidosis, hypoxia, heart failure

---

FRANK-STARLING LAW OF THE HEART

"The volume of blood ejected by the ventricle per beat is directly proportional to the end-diastolic volume (venous return)."

• Within physiological limits, the heart pumps all the blood returned to it
• Mechanism: More stretch → more overlap of actin-myosin → stronger contraction
• In steady state: CO = Venous Return
• This law ensures equal output from the left and right ventricles

• Upper curve (green): Positive inotropic effect - higher SV for same EDV
• Middle curve (purple): Normal (control)
• Lower curve (orange): Negative inotropic effect - lower SV for same EDV

---

FACTORS AFFECTING CARDIAC OUTPUT

A. Factors INCREASING CO:

B. Factors DECREASING CO:

---

REGULATION OF CARDIAC OUTPUT

1. Intrinsic Regulation (Frank-Starling Mechanism)

• Heart automatically adjusts to changes in venous return
• No external nervous input required
• Ensures equal output from both ventricles

2. Extrinsic Regulation (Autonomic Nervous System)

• Increased venous return stretches the right atrium → stretch of SA node → reflex ↑ HR
• Mediated via vagal afferents → vasomotor centre → sympathetic efferents back to SA node
• Increases HR by 10-15% → helps handle increased venous return

---

MEASUREMENT OF CARDIAC OUTPUT

1. Fick's Principle (Gold Standard)

CO = O₂ consumed per minute ÷ Arterio-venous O₂ difference

• O₂ absorbed by lungs = 200 mL/min
• Arterial blood O₂ = 200 mL/L; Venous blood O₂ = 160 mL/L
• A-V O₂ difference = 40 mL/L
• CO = 200 ÷ 40 = 5 L/min

---

2. Indicator Dilution Method (Stewart-Hamilton Method)

• A known amount of dye (e.g., indocyanine green / Cardiogreen) is injected into a central vein
• Concentration of dye is recorded as it passes through a peripheral artery
• CO is calculated from the time-concentration curve:

CO = Amount of indicator injected ÷ Area under dye-concentration curve

• Recirculation of dye must be corrected for by extrapolation of the downslope curve

---

3. Thermodilution Method (Most Widely Used Clinically)

• A known volume of cold saline is injected into the right atrium via a Swan-Ganz (pulmonary artery) catheter
• A thermistor at the tip of the catheter measures the temperature change in the pulmonary artery
• The greater the CO, the smaller and faster the temperature change
• CO is calculated using the Stewart-Hamilton equation for temperature change

---

4. Other Methods

• Echocardiography (Doppler): Non-invasive; measures aortic blood velocity and cross-sectional area
• Impedance cardiography: Uses thoracic electrical bioimpedance
• Pulse contour analysis: Continuous CO monitoring using arterial waveform
• Radionuclide ventriculography: Nuclear medicine - measures EF accurately

---

VENOUS RETURN AND ITS RELATIONSHIP TO CO

• In steady state: CO = Venous Return (what goes out must come back)
• Factors increasing venous return: skeletal muscle pump, respiratory pump (inspiration), venoconstriction, increased blood volume
• The primary controller of CO under normal resting conditions is venous return (peripheral factors), not the heart itself
• Only when venous return exceeds the heart's capacity does cardiac function become the limiting factor

---

SUMMARY OF IMPORTANT EQUATIONS

---

---

CARDIAC OUTPUT

(Chapter 95 - K. Sembulingam Style)

---

1. INTRODUCTION

---

2. DEFINITIONS AND NORMAL VALUES

A. STROKE VOLUME (SV)

• Volume of blood ejected by one ventricle per beat
• Normal value: 70 mL/beat (at rest)
• SV = End-Diastolic Volume (EDV) - End-Systolic Volume (ESV)
• Normal EDV = ~130 mL; Normal ESV = ~60 mL
• SV = 130 - 60 = 70 mL

B. MINUTE VOLUME (Cardiac Output)

• Volume of blood pumped by one ventricle per minute
• Formula: CO = SV × HR
• Normal CO = 70 mL × 72 beats/min = ~5000 mL/min (5 L/min)
• Also called minute volume of the heart
• Both right and left ventricles pump the same CO (in steady state)

C. CARDIAC INDEX (CI)

• CO varies with body size, so it is expressed per unit body surface area (BSA)
• Formula: CI = CO ÷ BSA
• Normal CI = 3.2 L/min/m² (range: 2.5 - 4.0 L/min/m²)
• BSA of average adult = ~1.7 m²
• CI is a better indicator for comparing individuals of different sizes
• Note: CI decreases with age - higher in infants and children

---

3. EJECTION FRACTION (EF)

• The percentage of EDV ejected per beat
• Formula: EF = (SV ÷ EDV) × 100
• EF = (70 ÷ 130) × 100 = ~55% (Normal: 55-70%)
• A direct measure of ventricular contractility (systolic function)
• EF < 40% = Heart failure with reduced EF (HFrEF)
• EF is measured by echocardiography, nuclear scan, or ventriculography

---

4. CARDIAC RESERVE

Cardiac Reserve = [(Maximum CO - Resting CO) ÷ Resting CO] × 100

• In health, large cardiac reserve allows the heart to increase output greatly during exercise, stress, fever, etc.
• In heart disease, reduced reserve means even mild exertion causes breathlessness and fatigue
• Exercise test (treadmill test) is used clinically to assess cardiac reserve - patients with low reserve develop dyspnea, fatigue, and excessive tachycardia rapidly

---

5. VARIATIONS IN CARDIAC OUTPUT

A. PHYSIOLOGICAL VARIATIONS

B. PATHOLOGICAL VARIATIONS

• Hyperthyroidism
• Anemia (↓ viscosity, reflex ↑ HR)
• Arteriovenous fistula / AV shunts
• Septicemia / septic shock (early, warm phase)
• Beri-beri (Vit B1 deficiency) - peripheral vasodilation
• Paget's disease of bone - ↑ vascularity of bone

• Heart failure (systolic dysfunction)
• Myocardial infarction
• Cardiac tamponade
• Cardiogenic shock
• Severe bradycardia / tachyarrhythmias
• Hemorrhage / hypovolemia
• Aortic stenosis / severe valvular disease
• Hypothyroidism

---

6. DISTRIBUTION OF CARDIAC OUTPUT

---

7. FACTORS MAINTAINING CARDIAC OUTPUT

A. VENOUS RETURN

• Most important factor maintaining CO
• CO = Venous Return in steady state (Frank-Starling law)
• Factors increasing venous return:
  • Skeletal muscle pump (exercise squeezes veins)
  • Respiratory pump (inspiration → negative intrathoracic pressure draws blood to right heart)
  • Venoconstriction (sympathetic stimulation)
  • Increased blood volume
  • Body position (lying down > standing)
• ↑ Venous Return → ↑ EDV → ↑ Stretch of ventricular muscle → ↑ Force of contraction → ↑ SV → ↑ CO (Frank-Starling Law)

B. FORCE OF CONTRACTION (Contractility / Inotropism)

• Intrinsic ability of myocardium to generate force
• Increased by (Positive Inotropes):
  • Sympathetic stimulation (β₁ adrenergic)
  • Catecholamines (adrenaline, noradrenaline)
  • Digoxin (cardiac glycoside)
  • Increased Ca²⁺
  • Treppe/Staircase effect (moderate ↑ HR)
• Decreased by (Negative Inotropes):
  • Parasympathetic stimulation
  • Hypoxia, acidosis, hypercapnia
  • Beta-blockers, Ca²⁺ channel blockers
  • Heart failure, ischemia

C. HEART RATE (Chronotropism)

• CO = SV × HR → so ↑ HR increases CO (up to a limit)
• At very high rates (>180 bpm): Diastolic filling time too short → EDV falls → SV falls → CO may decrease
• At very low rates (<40 bpm): Despite high SV, the product CO falls
• Optimal HR for maximum CO: ~120-150 bpm during exercise
• Controlled by:
  • SA node intrinsic rate
  • Autonomic NS: Sympathetic ↑ HR; Parasympathetic ↓ HR
  • Bainbridge reflex: ↑ venous return → stretch of SA node → ↑ HR

D. PERIPHERAL RESISTANCE (Afterload)

• The resistance the ventricle pumps against
• CO = MAP ÷ Total Peripheral Resistance (TPR)
• ↑ TPR (e.g., hypertension, aortic stenosis) → ↑ afterload → ↓ SV → ↓ CO
• ↓ TPR (e.g., vasodilation in exercise, sepsis, AV fistula) → ↓ afterload → ↑ CO
• Arterioles are the main site of peripheral resistance

---

8. MEASUREMENT OF CARDIAC OUTPUT

A. DIRECT METHODS

• Principle: "The amount of a substance taken up by an organ per unit time = Blood flow × arteriovenous concentration difference"
• Formula:

CO = O₂ consumed per minute ÷ (Arterial O₂ - Venous O₂)

• Example: O₂ consumption = 200 mL/min; Arterial O₂ = 200 mL/L; Venous O₂ = 160 mL/L
• CO = 200 ÷ 40 = 5 L/min
• Mixed venous blood taken from pulmonary artery; arterial blood from any systemic artery
• Most accurate but invasive; requires cardiac catheterization

---

B. INDIRECT METHODS

• A known quantity of dye (indocyanine green) or cold saline is injected into a vein/right atrium
• Concentration is measured downstream (peripheral artery)
• Formula: CO = Amount of indicator ÷ (Mean concentration × Duration of curve)
• Recirculation is corrected by extrapolating the downslope of the concentration-time curve

• Cold saline (known volume and temperature) injected into right atrium via Swan-Ganz catheter
• Thermistor at tip of catheter in pulmonary artery records temperature drop
• Greater the CO → smaller and shorter the temperature change
• Repeated measurements possible; no recirculation problem
• Errors: tricuspid regurgitation, intracardiac shunts, rapid IV fluids

• Non-invasive; measures aortic blood velocity × cross-sectional area of LVOT = SV
• CO = SV × HR
• Most commonly used in clinical practice today

• Non-invasive; measures changes in thoracic electrical impedance during cardiac cycle
• Changes in impedance reflect changes in blood volume in thorax

---

9. CARDIAC CATHETERIZATION

DEFINITION

CONDITIONS WHEN CARDIAC CATHETERIZATION IS PERFORMED

1. Coronary artery disease (angina, pre-bypass workup)
2. Valvular heart disease (stenosis or regurgitation - to assess severity)
3. Congenital heart disease (ASD, VSD, PDA - assess shunts and pressures)
4. Pulmonary hypertension (right heart catheterization)
5. Unexplained heart failure / dyspnea
6. Pre-operative cardiac assessment for major surgery
7. Pericardial disease (tamponade, constrictive pericarditis)
8. Before cardiac transplantation

PROCEDURE

• Catheter introduced via antecubital, femoral, subclavian, or jugular vein
• Advanced under fluoroscopic guidance: Right Atrium → Right Ventricle → Pulmonary Artery → Pulmonary Capillary Wedge Position (PCWP = surrogate for LA pressure)
• At each site: pressure measured + blood sample for O₂ saturation (screens for shunts)
• Swan-Ganz (balloon-tipped) catheter used - balloon inflated to float the catheter through tricuspid and pulmonary valves

• Catheter introduced via femoral or radial artery
• Advanced retrograde through aorta → across aortic valve → Left Ventricle
• Measures LV pressure, end-diastolic pressure
• Coronary angiography performed by injecting contrast into coronary ostia
• Alternatively via transseptal approach: needle punctures atrial septum at fossa ovalis (used for mitral valvuloplasty)

USES OF CARDIAC CATHETERIZATION

1. Diagnosis - measure intracardiac pressures, detect valvular gradients
2. Measure CO - via Fick's principle or thermodilution
3. Detect shunts - O₂ step-up in right heart chambers indicates left-to-right shunt
4. Coronary angiography - visualize coronary artery stenosis
5. Ventriculography - assess ventricular function, wall motion, EF
6. Therapeutic (interventional):

• Percutaneous Coronary Intervention (PCI/angioplasty + stenting)
• Balloon valvuloplasty (mitral, pulmonary)
• ASD/VSD device closure
• Transcatheter Aortic Valve Replacement (TAVR)

---