Deglutition Apnea - Duration

"Respiratory apnea associated with swallowing shows considerable variation across individuals, and in one study it ranged from 0.61 to 3.83 seconds."

Key Points

Mechanism

• Swallowing takes precedence over both respiration and mastication, briefly disrupting their rhythm.
• The respiratory center in the medulla is directly inhibited by the swallowing (deglutition) center during the pharyngeal phase.
• This apnea is essential for airway protection - the true vocal folds adduct simultaneously, preventing aspiration.
• The central pattern generator for swallowing is located in the caudal nucleus of the solitary tract (NST) and the medullary reticular formation adjacent to the nucleus ambiguus.
• Cummings Otolaryngology: Head and Neck Surgery, Oral Phase of Deglutition section

Physiology of High Atmospheric Pressure

1. Physical Principles (The Gas Laws)

• Medical Physiology (Boron & Boulpaep), p. 1791

2. Effect on Lung Volumes (Breath-Hold Diving)

• At 10 m (2 atm): lung volume → ½ of surface value
• At 20 m (3 atm): lung volume → ⅓
• At 30 m (4 atm): lung volume → ¼ (approximately residual volume)

3. Nitrogen Narcosis ("Rapture of the Deep")

• As depth increases, alveolar PN₂ rises and more N₂ dissolves into tissues (Henry's Law).
• N₂ is highly lipid-soluble and dissolves readily in neuronal membranes.
• It reduces ion conductance and neuronal excitability, mimicking general anesthesia.
• Onset: ~4-5 atm (about 30-40 m depth) breathing compressed air, after >1 hour.
• "Martini's Law": each 15 m of depth has the effect of drinking one additional martini.

1. Loss of psychosocial inhibitions (mild euphoria/intoxication)
2. Lethargy and drowsiness
3. Rapid onset of fatigue
4. Loss of consciousness (at extreme depth)

• Medical Physiology, p. 1795

4. Oxygen Toxicity

• Medical Physiology, p. 1796; Tintinalli's Emergency Medicine, Chapter 214

5. Nitrogen Saturation and Decompression Sickness ("The Bends")

Saturation

• At 1 atm normally: ~1 L of N₂ dissolved in body tissues (equally in water and fat compartments).
• At 4 atm: ultimately 4 L of N₂ dissolves (fat equilibrates slowly due to poor perfusion - takes hours).
• The longer and deeper the dive, the more N₂ saturates tissues.

Decompression Sickness (DCS)

• Symptoms begin minutes to several hours after surfacing (rarely, days later).
• Commercial/military/caisson workers: predominantly joint pain. Sport divers: more spinal cord involvement.
• Flying after diving can precipitate/worsen DCS (lower ambient pressure). Minimum wait: 12-24 hours.
• Patent foramen ovale increases risk of paradoxical gas embolism and neurological DCS.
• Treatment: Hyperbaric oxygen (HBO) recompression therapy - the only proven treatment.
• Tintinalli's Emergency Medicine, p. 1410-1411; Medical Physiology, p. 1797

6. Prevention: Helium-Oxygen (Heliox) Mixtures

1. Minimal narcotizing effect (far less lipid-soluble than N₂)
2. Less tissue dissolution (lower water/lipid solubility)
3. Lower density than N₂ - reduces airway resistance and work of breathing at depth
4. Faster washout on decompression (lower partition coefficient)

• Medical Physiology, p. 1797-1798

7. Barotrauma

• Middle ear barotrauma - most prevalent diving injury. Failure to equalize middle ear pressure via Eustachian tube causes pain, hemorrhage, membrane rupture.
• Sinus barotrauma - mucosal engorgement/hemorrhage in paranasal sinuses.
• Pulmonary squeeze - rare in breath-hold divers at extreme depth.

• Pulmonary overinflation syndrome - if diver ascends without exhaling, air expands to >2x lung volume, causing alveolar rupture.
• Complications: pneumothorax, pneumomediastinum, arterial gas embolism (AGE) - the most dangerous form.

8. Threshold Summary

Functions of Type I Pneumocytes (Type I Alveolar Cells)

Structure

Blood-Air Barrier - Electron Micrograph

Functions

1. Gas Exchange (Primary Function)

1. Type I alveolar cell (extremely thin cytoplasm, ~0.1-0.2 µm)
2. Fused basal laminae of Type I cell and capillary endothelium
3. Capillary endothelial cell (also thin)

2. Structural Integrity of the Alveolar Wall

• Type I cells provide the physical scaffold that maintains alveolar shape.
• Their wide, flat cytoplasmic extensions cover the alveolar surface and prevent collapse.
• The occluding (tight) junctions between Type I cells form an effective barrier between the air space and the septal wall components.

3. Fluid Barrier - Prevention of Pulmonary Edema

• The tight junctions between Type I cells prevent the passive movement of fluid and macromolecules from the interstitium into the alveolar air space.
• Type I cells also actively transport Na⁺ ions (via apical Na⁺ channels and basolateral Na⁺/K⁺-ATPase), which drives water reabsorption from the alveolar space - keeping alveoli dry and patent.

4. Passive Role in Surfactant Function

• Type I cells themselves do not produce surfactant.
• However, their flat surface provides the substrate on which the surfactant film (produced by Type II cells and club cells) spreads and functions to reduce surface tension.

5. Signal Transduction / Mechanosensing

• Type I cells contain numerous caveolae (small membrane invaginations) and are thought to play a role in mechanosensing - detecting stretch during lung inflation and potentially modulating downstream signaling.

Key Distinguishing Features vs. Type II Pneumocytes

Important: Type I cells cannot replicate

V/Q Ratio: Apex to Base of the Lung

Core Answer

The Classic West Data (Figure 10.19, Murray & Nadel)

• Apex: V/Q = 3.3 (high - relatively over-ventilated, under-perfused)
• Base: V/Q = 0.63 (low - relatively under-ventilated, over-perfused)
• Overall mean: ~0.8

Why Does This Happen? (Mechanism)

Gravity Drives Both Differences

• In the upright lung, intrapleural pressure is less negative at the base than the apex (gravity pulls the lung down, compressing the base).
• Basal alveoli start each breath at a smaller resting volume and are therefore on a steeper (more compliant) part of the pressure-volume curve.
• They expand more per unit pressure change - so they receive more ventilation.
• Apical alveoli start inspiration already more expanded (more negative intrapleural pressure) and are on the flatter portion of the compliance curve - so less additional volume enters per breath.

• Pulmonary circulation is a low-pressure system (mean ~15 mmHg), so gravity has a proportionally larger effect than in systemic circulation.
• Blood is pulled down by gravity. Pressure increases ~1 cmH₂O per cm of lung height.
• At the apex, arterial pressure may barely exceed alveolar pressure - capillaries are narrowed or barely open.
• At the base, both arterial and venous pressures exceed alveolar pressure - capillaries are fully open and distended.

• Ganong's Review of Medical Physiology, p. 632; Murray & Nadel's, p. 240

West Zones of Pulmonary Perfusion

• Morgan & Mikhail's Clinical Anesthesiology, p. 943-944

Consequences on Gas Exchange

• The net arterial PO₂ is determined largely by the base (which has most of the blood flow but lowest PO₂).
• The overall V/Q inequality causes arterial PO₂ to fall ~4 mmHg below what a perfectly homogeneous lung would achieve.
• A-a gradient exists partly because of this normal apex-to-base V/Q inequality.

"The base of the lung has most of the blood flow, but the PO₂ of the end-capillary blood is lowest there. As a result, the effluent pulmonary venous blood is loaded with moderately oxygenated blood from the base."

• Murray & Nadel's Textbook of Respiratory Medicine, p. 241

Note on Gravity Dependence

• Ganong's Review of Medical Physiology, p. 632

Topic 1: V/Q Inequality in ARDS and Pneumonia

The Core Mechanism

ARDS

1. Capillary leak - protein-rich fluid floods alveoli (alveolar edema)
2. Surfactant washout and inactivation - alveoli collapse (atelectasis)
3. Alveoli are flooded or collapsed - no ventilation occurs
4. Pulmonary blood flow continues to these non-ventilated units → V/Q = 0 (true shunt)

"Continued perfusion of alveoli that lack ventilation because of alveolar edema results in ventilation-perfusion ratios of zero, thereby defining physiologic shunt. Furthermore, the effects of this type of shunt are exacerbated by shunt-like contributions from alveoli with very low ventilation-perfusion ratios."

• Fishman's Pulmonary Diseases and Disorders, p. 2495

MIGET Studies (Multiple Inert Gas Elimination Technique) in ARDS:

• Only 52% of cardiac output flows to areas with normal V/Q
• Large shunt fraction + very low V/Q areas account for profound hypoxemia
• No diffusion limitation was found - all hypoxemia is V/Q-based
• Hypoxemia is resistant to supplemental O₂ (hallmark of shunt - you cannot ventilate collapsed/flooded alveoli)

Late ARDS (Proliferative/Fibroproliferative Phase):

• Dead space increases (fibrosis obliterates capillaries in some regions)
• Pulmonary hypertension develops
• High V/Q areas appear alongside existing low V/Q/shunt areas

Treatment Targets V/Q Directly:

• PEEP - opens atelectatic alveoli, converting shunt units to ventilated units → reduces shunt fraction
• Prone positioning - redistributes perfusion from collapsed dorsal segments to ventral ones, reducing shunt
• Inhaled vasodilators (e.g., NO) - selectively vasodilate ventilated regions → redirect blood away from shunt units

Pneumonia

• Consolidated lung (pus, fluid, inflammatory exudate filling alveoli) → no ventilation in affected region
• Surrounding, partially involved alveoli have reduced but not zero ventilation → low V/Q regions
• Blood flow to these areas continues → increased shunt + low V/Q units
• Hypoxic pulmonary vasoconstriction (HPV) is partially protective - it diverts blood away from hypoxic (consolidated) units. In pneumonia, inflammatory mediators partly blunt HPV, worsening shunt.

MIGET Data in Pneumonia (Murray & Nadel):

• As consolidation worsens, shunt fraction rises progressively
• Response to supplemental O₂ depends on degree of shunt (mild shunt responds; large shunt does not)

Comparison: ARDS vs Pneumonia vs PE

Topic 2: 2,3-DPG (2,3-Diphosphoglycerate / 2,3-BPG)

What Is 2,3-DPG?

Mechanism of Action

• 2,3-DPG has ~3.5 negative charges at physiological pH
• It binds to a central pocket formed by the two β-globin chains of deoxyhemoglobin, held by 8 positively charged amino acid residues
• This stabilizes the T (deoxy, low-affinity) state of hemoglobin
• O₂ binding changes the shape of this pocket, excluding 2,3-DPG → deoxy-Hb has 100× higher affinity for 2,3-DPG than oxy-Hb

• 2,3-DPG causes a right shift of the O₂-Hb dissociation curve
• P₅₀ (the PO₂ at which Hb is 50% saturated) increases
• At the tissue level (low PO₂), this markedly increases O₂ release
• At the alveolar level (high PO₂, flat part of curve), the reduction in O₂ loading is minimal

When Does 2,3-DPG Increase?

"Chronic hypoxia, anemia, and acclimation to high altitude are all associated with an increase in 2,3-DPG levels and thus lower the O₂ affinity of Hb."

• Medical Physiology, p. 958

When Does 2,3-DPG Decrease?

Clinical Significance: The Two-Edged Sword

"Reducing the [O₂] affinity is a two-edged sword. At the relatively high PO₂ in alveoli, where the Hb-O₂ dissociation curve is fairly flat, this decrease in O₂ affinity reduces O₂ uptake - but only slightly. At the low PO₂ in systemic tissues, where the Hb-O₂ dissociation curve is steep, this decrease in O₂ affinity markedly increases the O₂ release. The net effect is enhanced O₂ unloading to metabolizing tissues."

• Medical Physiology, p. 958

Right and Left Shifts of the O₂-Haemoglobin Dissociation Curve

The Curve and P₅₀

• P₅₀ increases → right shift (lower affinity, more O₂ released)
• P₅₀ decreases → left shift (higher affinity, less O₂ released)

The Shifts - Classic Diagram

RIGHT SHIFT

LEFT SHIFT

The Bohr Effect (Most Important Right-Shift Mechanism)

"Both hydrogen ions and carbon dioxide bind at sites on the hemoglobin molecule that differ from the oxygen-binding sites. There are many more sites that bind hydrogen ions than bind CO₂ molecules. As the tertiary and quaternary configurations of the hemoglobin molecule change with release of oxygen, 16 of these hydrogen-binding sites change their physiologic buffering capacities."

• Fishman's Pulmonary Diseases and Disorders, p. 2374

• Cells produce CO₂ → CO₂ enters RBC → carbonic anhydrase converts to H⁺ + HCO₃⁻
• ↑ H⁺ + ↑ PCO₂ → right shift → Hb releases O₂ to the very tissue that needs it

• CO₂ expelled → ↓ PCO₂ → ↑ pH → left shift → Hb loads O₂ from alveolar air

Carbon Monoxide - A Special Case

• CO binds heme with 250× greater affinity than O₂ (Costanzo) / 200× greater (Boron & Boulpaep)
• Blocks O₂ binding sites → functional anaemia (reduced O₂ capacity)
• The remaining unbound heme sites have increased O₂ affinity → left shift → O₂ that IS carried is not released to tissues
• Together these effects are catastrophic for O₂ delivery

Summary Table

Mnemonic: CADET (Right Shift)

Right and Left Shifts In the Lungs

The Key Point

What Happens in the Pulmonary Capillaries

"All of the reactions previously described occur in reverse in the lungs. H⁺ is released from its buffering sites on deoxyhemoglobin, HCO₃⁻ enters the red blood cells in exchange for Cl⁻, H⁺ and HCO₃⁻ combine to form H₂CO₃, and H₂CO₃ dissociates into CO₂ and H₂O. The regenerated CO₂ and H₂O are expired by the lungs."

• Costanzo Physiology, 7th Ed., p. 231

The Bohr Effect: Tissues vs Lungs

The Haldane Effect - The Complementary Mechanism

"Binding of O₂ with hemoglobin in the lungs causes hemoglobin to become a stronger acid. This displaces CO₂ from the blood. The Haldane effect is quantitatively far more important in promoting CO₂ transport than the Bohr effect is in promoting O₂ transport."

• Guyton & Hall Textbook of Medical Physiology

• OxyHb is a stronger acid than deoxyHb
• As O₂ binds Hb in the lungs → Hb becomes more acidic → releases H⁺
• H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O → CO₂ exhaled
• OxyHb also binds CO₂ (carbamino) less avidly → more CO₂ released

• O₂ loading causes CO₂ unloading (Haldane)
• CO₂ unloading causes O₂ loading (reverse Bohr)

When a Right Shift Is Problematic in the Lungs

"The right shift is advantageous in the tissues because it is associated with increased P₅₀, decreased affinity, and increased unloading of O₂. However, the right shift is disadvantageous in the lungs because it becomes more difficult to load the pulmonary capillary blood with O₂."

• Costanzo Physiology, 7th Ed., p. 232

Summary

Hering-Breuer Reflex and J Receptors

Part 1: The Hering-Breuer Reflex

Discovery and Basis

Receptor: Slowly Adapting Pulmonary Stretch Receptors (SAPSRs)

• Located in the smooth muscle of bronchi and bronchioles throughout the lung
• Myelinated afferent fibres
• Respond to stretch/lung inflation with sustained firing (slow adaptation - firing persists as long as lung remains inflated)
• Afferents travel to the dorsal respiratory group of neurons in the medulla via the vagus nerve (CN X)

The Hering-Breuer Inflation Reflex

1. Lung inflates during inspiration → airways/bronchi stretch
2. SAPSRs fire → signals travel via vagus to DRG (dorsal respiratory group) of medulla
3. Inspiratory ramp is "switched off" → inspiration terminates
4. Expiration begins

"When the lungs become overinflated, the stretch receptors activate a feedback response that 'switches off' the inspiratory ramp and stops further inspiration."

• Guyton & Hall Textbook of Medical Physiology

• ↑ Duration of expiration (longer expiratory pause)
• ↑ Respiratory frequency (by shortening inspiration time)
• Maintains constant alveolar ventilation

The Hering-Breuer Deflation Reflex

• Marked deflation of the lung → decreased SAPSR firing → decrease in duration of expiration → promotes next inspiration
• Protective against over-deflation

Threshold - Adults vs Infants

"In humans, the Hering-Breuer reflex probably is not activated until the tidal volume increases to more than three times normal (~1.5 L/breath). Therefore, this reflex appears to be mainly a protective mechanism for preventing excess lung inflation rather than an important factor in normal control of ventilation."

• Guyton & Hall, p. 533

Proof - Vagotomy

Summary of Hering-Breuer

Part 2: J Receptors (Juxtacapillary Receptors)

What Are They?

"Alveolar C-fiber receptors become active very soon (1-2 seconds) after injection of certain chemicals into the blood of the right atrium of the heart, which suggests that the receptors may be very near pulmonary capillaries. Hence the name juxtacapillary or J receptors."

• Medical Physiology (Boron & Boulpaep), p. 1071

Location

• In the alveolar walls and interstitium
• Very close to pulmonary capillaries
• Afferent fibres are unmyelinated C fibres → conduct slowly (even at 4°C, unlike myelinated fibres which are blocked by cooling)
• Travel to medulla via vagus nerve

Stimuli (What Activates J Receptors?)

Reflex Response - "Pulmonary Chemoreflex"

1. Apnea (brief cessation of breathing) - first response
2. Followed by rapid, shallow breathing (tachypnea)
3. Bradycardia
4. Hypotension
5. Bronchoconstriction
6. Increased mucus secretion

"The reflex response that is produced is apnea followed by rapid breathing, bradycardia, and hypotension (pulmonary chemoreflex)."

• Ganong's Review of Medical Physiology

Physiological and Clinical Significance

Comparison: Three Types of Pulmonary Receptors

Bezold-Jarisch Reflex

History and Definition

Bradycardia + Hypotension + Apnea (followed by rapid shallow breathing)

Reflex Arc

Receptor

• Chemoreceptors and mechanoreceptors in the left ventricular wall (inferoposterior region preferentially)
• Also in: atria, great veins, pulmonary artery, juxtacapillary (J receptor) region of alveoli
• These are collectively called cardiopulmonary chemosensitive receptors

Afferent Limb

• Unmyelinated vagal C fibres → travel to the nucleus tractus solitarius (NTS) in the medulla

Efferent Limb

• Increased parasympathetic (vagal) tone to the heart → bradycardia
• Withdrawal of sympathetic tone to resistance vessels → vasodilation and hypotension
• Coronary artery dilation

Stimuli That Activate the Reflex

Classic Triad of Responses

"The Bezold-Jarisch reflex responds to noxious ventricular stimuli sensed by chemoreceptors and mechanoreceptors within the left ventricular wall by inducing the triad of hypotension, bradycardia, and coronary artery dilatation."

• Miller's Anesthesia, 10th Ed.

Clinical Significance

1. Vasovagal Syncope (Most Common Clinical Context)

• Prolonged upright posture / dehydration → blood pools in lower limbs → reduced ventricular filling
• Under-filled but vigorously contracting left ventricle → activates ventricular mechanoreceptors
• Paradoxical reflex: instead of tachycardia, ventricular receptors trigger bradycardia + vasodilation
• Massive parasympathetic discharge + sympathetic withdrawal → profound fall in BP and HR
• Cerebral perfusion drops → loss of consciousness

"Pressure receptors in the wall of the left ventricle respond by sending signals that trigger paradoxical bradycardia and decreased contractility, resulting in sudden marked hypotension."

• Ganong's Review of Medical Physiology

2. Inferior/Posterior Myocardial Infarction

• Occlusion of the right coronary artery (which supplies the inferoposterior LV wall) → activation of ventricular receptors
• Produces bradycardia + hypotension seen in inferior MI (the classic "vagal MI")
• Thought to be cardioprotective - coronary dilation may improve collateral perfusion

3. Coronary Angiography

• Injection of radiocontrast into coronary arteries → activates ventricular receptors → bradycardia + hypotension during the procedure

4. Thrombolysis / Reperfusion

• Release of oxygen radicals and serotonin during reperfusion injury activates the reflex
• Contributes to reperfusion hypotension and bradycardia

5. Spinal Anaesthesia

• Sympathetic blockade → venous pooling → reduced ventricular filling → Bezold-Jarisch activation
• Important cause of severe bradycardia/asystole during spinal anaesthesia (estimated 2-3 per 10,000 anaesthetic procedures)

Relationship to Vasovagal Syncope Mechanism

Emotional stress / standing / blood loss
           ↓
Reduced ventricular filling
           ↓
Vigorous contraction of under-filled LV
           ↓
Activation of LV inferoposterior mechanoreceptors
           ↓
C-fibre vagal afferents → NTS → medulla
           ↓
↑ Parasympathetic + ↓ Sympathetic output
           ↓
Bradycardia + Vasodilation + ↓ Cardiac output
           ↓
↓ Mean arterial pressure → Cerebral hypoperfusion
           ↓
Syncope (loss of consciousness in ~10 seconds)

Modulation

• ANP/BNP (natriuretic peptides): Stimulate receptors that can modulate the reflex
• Cardiac hypertrophy / atrial fibrillation: Reflex may be attenuated
• Atropine: Blocks the bradycardia component (but does not reliably prevent vasovagal syncope since the vasodilatory component persists)
• β-blockers / disopyramide: Used to reduce syncope episodes
• IV fluids / salt loading / fludrocortisone: Prevent by increasing ventricular filling

Summary Table

Heterometric and Homometric Regulation of the Heart

1. Heterometric Regulation (Length-Dependent)

Definition

"When cardiac output is regulated by changes in cardiac muscle fiber length, this is referred to as heterometric regulation."

• Ganong's Review of Medical Physiology

Basis: Frank-Starling Law

• The heart muscle behaves like skeletal muscle: the more it is stretched before contraction (preload), the greater the force of contraction
• Starling stated: "The energy of contraction is proportional to the initial length of the cardiac muscle fibre"
• The key variable is end-diastolic volume (EDV) → determines fibre length before systole

Molecular Mechanism

1. ↑ Preload → ↑ EDV → ↑ sarcomere length at end-diastole
2. Greater sarcomere stretch → ↑ myofilament Ca²⁺ sensitivity (troponin C binds Ca²⁺ more avidly)
3. Narrowing of interfilament spacing at longer lengths may enhance cross-bridge formation
4. More cross-bridges formed → ↑ force generated per beat → ↑ stroke volume

"There is also a substantial increase in myofilament Ca²⁺ sensitivity with an increase in sarcomere length... the myocyte is at constant volume, so as the cell shortens it must thicken, and conversely, when stretched, the cell becomes thinner and filament spacing becomes narrower."

• Braunwald's Heart Disease

Examples in Physiology

Frank-Starling Curve

• X-axis: End-diastolic volume (or filling pressure/preload)
• Y-axis: Stroke volume (or cardiac output)
• Rising limb: Optimal filament overlap and Ca²⁺ sensitivity
• Descending limb: Excessive stretch, reduced overlap (seen in severe heart failure)

2. Homometric Regulation (Length-Independent)

Definition

"Regulation due to changes in contractility independent of length is sometimes called homometric regulation."

• Ganong's Review of Medical Physiology

"Conditions in which contraction is strengthened independent of sarcomere length (e.g., typically by increased Ca²⁺ transient amplitude) are referred to as positive inotropic states or enhanced contractility."

• Braunwald's Heart Disease

Mechanism

• Changes in the amplitude of the intracellular Ca²⁺ transient (how much Ca²⁺ is released per beat from the SR)
• More Ca²⁺ per beat → more troponin C binding → more cross-bridges → more force - at the same fibre length
• Measured as a shift of the Frank-Starling curve upward (better performance at the same preload)

Examples of Homometric Regulation

A. Sympathetic / Catecholamine Stimulation (most important)

• Noradrenaline/adrenaline → β₁ receptors → ↑ cAMP → PKA activation
• PKA phosphorylates L-type Ca²⁺ channels → ↑ Ca²⁺ influx per action potential
• PKA phosphorylates phospholamban → ↑ SR Ca²⁺ reuptake and storage → larger Ca²⁺ store
• Net: ↑ Ca²⁺ transient amplitude → ↑ force at same length = positive inotropy
• Chronotropic action (↑ HR) is a separate effect

B. Bowditch Effect / Treppe Phenomenon (Force-Frequency Relationship)

"An increased HR progressively enhances the force of ventricular muscle contraction... the Bowditch staircase phenomenon (treppe = German for 'steps')"

• Braunwald's Heart Disease

• ↑ Heart rate → more action potentials per minute → more Ca²⁺ entry per unit time, less time to extrude Ca²⁺ → ↑ intracellular [Ca²⁺] → ↑ force per beat
• Peaks at ~150-180 bpm; declines at very high HR (insufficient diastolic filling time)
• Clinically important during exercise

C. Anrep Effect (Homeometric Adaptation to Afterload)

"When the aortic pressure is elevated abruptly, ejection is limited, tending to increase EDV, which acutely increases force by the Frank-Starling effect. However, in a slower adaptation (seconds to minutes), the inotropic state of the heart increases (larger Ca²⁺ transients). This slow force response is referred to as the Anrep effect."

• Braunwald's Heart Disease

• Acute ↑ afterload → initially heterometric response (Starling) - brief
• Then slower homometric response: stretch-induced autocrine/paracrine signalling → ↑ Ca²⁺ transients via NOS1/CaMKII pathway
• Allows heart to maintain output against higher pressure without persistently increasing fibre length
• Important for RV adaptation to pulmonary hypertension: RV hypertrophies and increases contractility without enlarging (homeometric/homometric)

D. Pharmacological Inotropes

Comparison Summary

Clinical Relevance

Heart Blocks (AV Blocks)

Anatomy of AV Conduction

• AV node → Bundle of His → Left and Right bundle branches → Purkinje fibres

Causes of AV Block

Classification

1st Degree AV Block

• Every P wave is followed by a QRS (1:1 conduction maintained)
• PR interval typically 0.20-0.35 sec (can reach 0.45 sec)
• QRS usually narrow (normal)
• Rhythm: regular

• Normal variant in up to 2% of healthy young adults
• May be caused by increased vagal tone (athletes)
• Alone: benign, no specific treatment
• Indicates increased susceptibility if caused by drugs/disease

2nd Degree AV Block

Mobitz Type I (Wenckebach)

• Progressive PR interval lengthening beat-to-beat
• Until one P wave is not followed by a QRS (dropped beat)
• After the dropped beat, PR interval resets to shortest value → cycle repeats
• QRS: narrow (usually)
• Grouped beating pattern (e.g., 3:2, 4:3, 5:4)
• RP/PR reciprocity: shorter RP → longer PR

Mobitz Type II

• Fixed PR interval (does NOT progressively prolong)
• Sudden, unexpected dropped beats - P waves not followed by QRS
• Conduction ratio fixed: 2:1, 3:1, 3:2, etc.
• QRS often wide (bundle branch block present)

2:1 AV Block - Diagnostic Challenge

• Every alternate P wave is blocked - cannot tell if Mobitz I or II from rhythm alone
• Wide QRS → likely Mobitz II (infranodal)
• Prolonged PR → likely Mobitz I (nodal)
• May require electrophysiology study to determine level

3rd Degree (Complete) AV Block

• P waves and QRS complexes are completely independent - no fixed relationship
• Atrial rate: normal (~60-100 bpm)
• Ventricular rate: slow escape rhythm (determined by site of escape pacemaker)
• R-R interval > P-P interval (ventricular rate slower than atrial rate)

Stokes-Adams Syndrome

• Sudden loss of consciousness (syncope)
• Seizure-like activity (cerebral anoxia)
• Pallor then flushing on recovery
• No warning, immediate loss then rapid recovery
• Managed with permanent pacemaker

Comparison Table: All Degrees

Bundle Branch Blocks (Related Conduction Defects)

Management Principles

Acromegaly and Gigantism

The Fundamental Distinction

"All body tissues grow rapidly, including the bones. If the condition occurs before adolescence, before the epiphyses of the long bones have fused, height increases so that the person may develop gigantism and become up to 8 feet tall." - Guyton & Hall

Pathophysiology

• Pituitary somatotroph adenoma → uncontrolled GH hypersecretion
• GH → liver → IGF-1 (Insulin-like Growth Factor-1) - the main effector
• IGF-1 promotes growth of bone, soft tissue, and viscera
• Normal feedback (IGF-1 → inhibits GH via somatostatin) is bypassed

• Symptoms are subtle and insidious - average diagnostic delay of 10+ years
• 75% are macroadenomas by time of presentation
• First clue may be "large, enveloping, doughy handshake" or voice changes

• Ectopic GHRH production: bronchial/abdominal carcinoid tumors, small cell lung cancer, medullary thyroid cancer, phaeochromocytoma
• Ectopic GH: islet cell tumors, lymphomas
• MEN1 syndrome (menin mutation) - 10% of tumors secrete GH

Gigantism - Clinical Features

Acromegaly - Characteristic Features (System by System)

Facial and Head Features (Hallmarks)

Hands and Feet (Classic Acral Changes)

• Increased ring, shoe, glove, and hat size (patients often notice this first)
• Fingers broad and spade-shaped - fingertips resemble drumsticks
• Feet require size 14+ shoes
• Hands almost twice normal size
• Increased heel pad thickness (visible on lateral X-ray)

Skin Changes

Musculoskeletal

Cardiovascular (Most Important for Prognosis)

• Left ventricular hypertrophy (biventricular cardiomegaly)
• Cardiomyopathy - systolic and diastolic dysfunction
• Hypertension (common) - volume expansion + direct vascular GH effects
• Arrhythmias
• Heart failure
• Premature coronary artery disease - via hypertension, dyslipidaemia, insulin resistance
• Overall mortality increased threefold, primarily from CV and cerebrovascular disease
• Survival reduced by ~10 years if GH levels uncontrolled

Respiratory

• Obstructive sleep apnoea (OSA) - occurs in >60% of patients
  • Soft tissue pharyngeal/laryngeal overgrowth
  • Central sleep dysfunction component
• Macroglossia contributes to upper airway obstruction
• Subglottic narrowing possible → important for anaesthetists (difficult intubation)

Metabolic and Endocrine

GI and Oncological

• Colonic polyps - up to 1/3 of patients
• Colon cancer - increased mortality; skin tags are a marker
• Visceromegaly - liver, kidneys, thyroid, salivary glands, spleen all enlarged

Neurological

• Headache - in up to 60% (direct tumour effect, not just mass)
• Bitemporal hemianopia - chiasmal compression by macroadenoma (10% at presentation)
• Cranial nerve palsies - with cavernous sinus invasion
• Peripheral neuropathy
• Hypersomnia

Summary Comparison

Diagnosis

• Normal: GH suppresses to <0.4 µg/L (ultrasensitive assay) or <1 µg/L (immunoassay)
• Acromegaly: GH fails to suppress (remains elevated or paradoxically rises in ~20%)
• Random GH is unreliable due to pulsatile secretion

Treatment