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Respiratory Physiology: Basics to Clinicals

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1. Overview and Goals of the Respiratory System

• Humidification and filtration of inspired air
• Acid-base regulation (via CO₂ excretion)
• Phonation (speech)
• Pulmonary defense (mucociliary clearance, alveolar macrophages)
• Metabolic functions (conversion of angiotensin I → II; inactivation of bradykinin, serotonin)

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2. Anatomy of the Respiratory System

Conducting Zone (Dead Space)

• Nose → pharynx → larynx → trachea → bronchi → bronchioles → terminal bronchioles
• No gas exchange occurs here - this constitutes the anatomical dead space (~150 mL)
• Functions: warm, humidify, filter air; mucociliary escalator clears particles

Respiratory Zone (Gas Exchange)

• Respiratory bronchioles → alveolar ducts → alveolar sacs → alveoli
• ~300 million alveoli; total surface area = 50-100 m²
• Alveolar wall consists of:
  • Type I pneumocytes (95% of surface) - thin, for gas diffusion
  • Type II pneumocytes (5% of surface) - produce surfactant (dipalmitoyl phosphatidylcholine, DPPC), can regenerate Type I cells
  • Alveolar macrophages - first-line defense

The Respiratory Membrane

1. Alveolar fluid layer (surfactant)
2. Alveolar epithelium (Type I cell)
3. Epithelial basement membrane
4. Thin interstitial space
5. Capillary basement membrane
6. Capillary endothelium

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3. Lung Volumes and Capacities

• FRC = the volume at end of passive expiration where inward lung recoil = outward chest wall recoil. RV cannot be measured by spirometry alone.
• FEV₁/FVC ratio: normal ≥0.70
  • Obstructive (asthma, COPD): FEV₁↓, FVC normal/↓, ratio <0.70; TLC↑, RV↑
  • Restrictive (fibrosis, pleural effusion): FEV₁↓, FVC↓, ratio normal or ↑; TLC↓

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4. Lung Mechanics

4a. Pressures

• Atmospheric pressure: 760 mm Hg (reference = 0 cmH₂O)
• Pleural (intrapleural) pressure: normally -5 cmH₂O at rest; becomes -7.5 cmH₂O during inspiration. This negative pressure holds the lung against the chest wall.
• Alveolar pressure: 0 cmH₂O at rest; -1 cmH₂O during inspiration (air flows in); +1 cmH₂O during expiration (air flows out)
• Transpulmonary pressure = Alveolar - Pleural = the pressure that keeps the lung open

Pneumothorax (air in pleural space) eliminates the negative pleural pressure → lung collapses.

4b. Compliance

• ↑ Compliance (easier to inflate): emphysema (loss of elastic recoil), aging
• ↓ Compliance (stiffer): pulmonary fibrosis, ARDS, pulmonary edema, neonatal RDS (surfactant deficiency)

4c. Surface Tension and Surfactant

• Small alveoli would collapse into large ones (atelectasis)
• Much greater work of breathing would be needed

4d. Airway Resistance

• Determined primarily by medium-sized bronchi (not the tiny bronchioles which are too numerous, or the large airways)
• ↑ Resistance: bronchospasm (asthma), mucus plugging, foreign body
• Sympathetics (β₂ stimulation) → bronchodilation
• Parasympathetics (ACh, M₃) → bronchoconstriction
• Histamine, leukotrienes → bronchoconstriction

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5. Pulmonary Circulation

• Mean pulmonary arterial pressure: 15 mm Hg (vs. 100 mm Hg systemic)
• Pulmonary capillary wedge pressure (PCWP): ~7 mm Hg
• Pulmonary vascular resistance (PVR): very low

• Hypoxic pulmonary vasoconstriction (HPV): When PO₂ in an alveolus drops, the adjacent blood vessels constrict - this is the opposite of systemic vessels. HPV diverts blood away from poorly ventilated areas to better-ventilated ones, optimizing V/Q matching.
• Zone model (West's Zones): Blood flow varies throughout the lung based on the relationship between PA (alveolar), Pa (arterial), and Pv (venous) pressures:
  • Zone 1 (apex): PA > Pa > Pv → capillaries can collapse → dead space (not normally present)
  • Zone 2 (mid): Pa > PA > Pv → flow determined by Pa - PA
  • Zone 3 (base): Pa > Pv > PA → flow determined by Pa - Pv (highest flow)

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6. Gas Exchange - Diffusion

Dalton's Law (Partial Pressures)

• PO₂ = 0.21 × 760 = 160 mm Hg
• PCO₂ = 0.0004 × 760 = 0.3 mm Hg

• PO₂ = 0.21 × (760-47) = ~150 mm Hg (inspired)
• Alveolar PO₂ ~104 mm Hg (after mixing with alveolar gas and CO₂ addition)

Alveolar Gas Equation

• ↑ A-a gradient → problem with diffusion, V/Q mismatch, or shunt
• Normal A-a gradient with hypoxia → hypoventilation or low FiO₂

Fick's Law of Diffusion

• CO₂ is 20 times more soluble than O₂ → diffuses far more easily despite having same or lower partial pressure gradient
• Normal diffusing capacity for O₂ (DLCO) = ~21 mL/min/mmHg at rest; triples during exercise

• Emphysema (↓ surface area)
• Pulmonary fibrosis (↑ thickness)
• Pulmonary hypertension (↓ perfusion)
• Anemia (↓ Hb)

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7. Ventilation-Perfusion (V/Q) Relationships

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8. Oxygen Transport in Blood

Dissolved O₂

Hemoglobin-Bound O₂ (98.5%)

• Hb carries O₂ as oxyhemoglobin
• Each Hb molecule has 4 heme groups → carries up to 4 O₂ molecules
• Fully saturated Hb carries 1.34 mL O₂/g Hb
• At normal Hb (15 g/dL): O₂ content = 15 × 1.34 × 0.98 + 0.3 = ~20 mL O₂/dL

Oxyhemoglobin Dissociation Curve (ODC)

• P50 (PO₂ at 50% saturation) = 26.8 mmHg normally
• Flat upper portion (PaO₂ 60-100 mmHg): protects against drops in PO₂ (SaO₂ stays >90% even if PaO₂ falls from 100→60)
• Steep lower portion (PaO₂ 20-60 mmHg): O₂ readily unloads to tissues

• ↑ PCO₂
• ↑ Temperature
• ↑ H⁺ (↓ pH/acidosis)
• ↑ 2,3-DPG (chronic hypoxia, anemia)

• ↓ PCO₂, ↓ H⁺ (alkalosis), ↓ Temperature
• Carbon monoxide (CO) - 240× affinity for Hb vs O₂ → cherry-red color, carboxyhemoglobin
• Fetal hemoglobin (HbF) - has γ chains instead of β; less 2,3-DPG binding → higher O₂ affinity (good for fetal O₂ uptake across placenta)
• Methemoglobin (oxidized Fe³⁺)

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9. CO₂ Transport

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10. Acid-Base Balance and Respiratory Contribution

• Metabolic acidosis → hyperventilation → ↓ PaCO₂ (Kussmaul breathing in DKA)
• Metabolic alkalosis → hypoventilation → ↑ PaCO₂

Acid-Base Disorders

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11. Control of Breathing

Brainstem Centers

1. Dorsal Respiratory Group (DRG) - medulla - controls inspiration rhythm; sends output via phrenic nerve (C3,4,5) to diaphragm; receives input from CN IX (glossopharyngeal) and CN X (vagus)
2. Ventral Respiratory Group (VRG) - medulla - inactive during quiet breathing; activated during forced expiration (exercise)
3. Pneumotaxic Center (upper pons) - turns OFF inspiration, limits tidal volume, regulates respiratory rate
4. Apneustic Center (lower pons) - excites inspiratory center; stimulation → prolonged inspiratory gasps (apneusis); normally inhibited by pneumotaxic center

Chemoreceptors

• Located on ventral surface of medulla
• Respond to changes in CSF pH/PCO₂ (CO₂ freely diffuses across blood-brain barrier → forms H⁺)
• Most important for minute-to-minute control of ventilation
• Not directly sensitive to O₂

• Carotid bodies (CN IX - most important) and aortic bodies (CN X)
• Respond to: ↓ PaO₂ (<60 mmHg), ↑ PaCO₂, ↓ pH
• Primary stimulus in patients with chronic hypercapnia (COPD) who have lost CO₂ sensitivity → "hypoxic drive" (caution with high-flow O₂)
• Also respond to: cyanide, hypotension, severe anemia

• PaCO₂: most potent stimulus; ↑ by 1 mmHg → ↑ ventilation by ~3 L/min
• pH: acidosis stimulates breathing (partially independent of PaCO₂)
• PaO₂: weak stimulus until PaO₂ drops below 60 mmHg (below the flat part of ODC)

Lung Reflexes (Stretch Receptors)

• Hering-Breuer Inflation Reflex: pulmonary stretch receptors (in smooth muscle) → via vagus → inhibit inspiration when lungs overdistended (prevents over-inflation)
• Deflation reflex: stimulates inspiration when lungs collapse
• Irritant receptors (rapidly adapting): cough, bronchoconstriction in response to chemicals/particulates
• J receptors (juxtacapillary, C-fibers): activated by pulmonary edema, emboli → rapid shallow breathing, dyspnea

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12. Applied / Clinical Correlations

12a. Hypoxemia - Five Mechanisms

12b. COPD

• Emphysema: ↓ elastic recoil, ↑ compliance, ↑ TLC/RV, ↓ DLCO (destroyed alveolar surface), airway collapse on expiration (dynamic hyperinflation), barrel chest
• Chronic bronchitis: excess mucus, ↑ airway resistance, V/Q mismatch
• FEV₁/FVC < 0.70 is diagnostic criterion
• "Pink puffer" (emphysema): maintains near-normal PaO₂ by hyperventilating; dyspnea prominent, thin
• "Blue bloater" (chronic bronchitis): hypercapnia, polycythemia, cor pulmonale, edema

12c. Asthma

• Reversible airway obstruction: ↑ resistance, air trapping, ↑ RV
• Triggers: allergens, exercise, cold air, irritants
• Pathology: airway inflammation, smooth muscle hypertrophy, mucus plugging
• Treatment: β₂-agonists (bronchodilation via cAMP), inhaled corticosteroids, leukotriene antagonists

12d. Restrictive Lung Disease

• ↓ TLC, ↓ VC, ↓ FVC; FEV₁/FVC normal or ↑
• Causes: pulmonary fibrosis (IPF), sarcoidosis, pneumoconiosis, pleural effusion, kyphoscoliosis, obesity, neuromuscular disease (ALS, myasthenia gravis)
• IPF: progressive fibrosis, Velcro crackles, clubbing, ↓ DLCO → lung transplant

12e. Pulmonary Embolism (PE)

• Clot occludes pulmonary artery → dead space ↑ (V/Q → ∞)
• Hypoxemia due to V/Q mismatch in rest of lung + reflex bronchoconstriction
• Classic presentation: sudden dyspnea, pleuritic chest pain, tachycardia
• ABG: hypoxia + hypocapnia (hyperventilation), ↑ A-a gradient
• Wells score for pretest probability; CT-PA for diagnosis; anticoagulation for treatment

12f. ARDS (Acute Respiratory Distress Syndrome)

• Diffuse alveolar damage → protein-rich edema → ↓ compliance, ↓ DLCO, severe hypoxemia (shunt)
• Berlin criteria: acute onset <1 week, bilateral infiltrates, PaO₂/FiO₂ ≤300 (mild), ≤200 (moderate), ≤100 (severe), not fully explained by heart failure
• Treatment: lung-protective ventilation (6 mL/kg tidal volume, PEEP to open collapsed alveoli), prone positioning in severe ARDS

12g. Pulmonary Hypertension

• Mean PAP >20 mmHg at rest
• Causes: idiopathic (IPAH, PAH), left heart failure (Group 2), chronic hypoxia/COPD (Group 3), PE (Group 4)
• Chronic hypoxia → sustained HPV → remodeling → fixed pulmonary hypertension → right heart failure (cor pulmonale)
• Treatment of PAH: phosphodiesterase-5 inhibitors (sildenafil), prostacyclin analogues, endothelin receptor antagonists

12h. Respiratory Failure

12i. High Altitude Physiology

• ↓ Barometric pressure → ↓ PiO₂ → hypoxemia → hyperventilation (respiratory alkalosis)
• Compensations over days-weeks:
  • ↑ EPO → polycythemia
  • ↑ 2,3-DPG → rightward shift of ODC
  • Renal HCO₃⁻ excretion to normalize pH
  • ↑ pulmonary vasodilation (locally)
• Acute Mountain Sickness (AMS): headache, nausea at altitude; treated with acetazolamide (carbonic anhydrase inhibitor → forced bicarbonate diuresis → metabolic acidosis → drives ventilation)

12j. CO₂ Narcosis and Oxygen Therapy in COPD

• Use controlled O₂ (24-28% Venturi mask) targeting SpO₂ 88-92% in acute exacerbations of COPD.

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13. Key Numbers to Remember

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Sources

• Guyton and Hall Textbook of Medical Physiology (14th ed.) - Chapters 38-41
• Costanzo Physiology (7th ed.) - Chapter 5
• Ganong's Review of Medical Physiology (26th ed.) - Section VI
• Fishman's Pulmonary Diseases and Disorders (5th ed.)

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Renal Anatomy and Physiology: Basics to Clinicals

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1. Renal Anatomy

Gross Anatomy

• Two kidneys lie retroperitoneally on either side of the vertebral column at T12-L3
• Dimensions: ~11 cm long, 6 cm wide, 3 cm thick; each weighs ~150 g
• The right kidney sits slightly lower due to the liver
• Each kidney is surrounded by perirenal fat, renal (Gerota's) fascia, and pararenal fat

• Cortex (outer): contains glomeruli, proximal and distal convoluted tubules, cortical collecting ducts - pale in color
• Medulla (inner): contains loops of Henle, collecting ducts - forms 8-18 pyramid-shaped renal pyramids
• Renal columns of Bertin: cortical tissue extending between pyramids
• Renal papillae: tips of pyramids, where collecting ducts (of Bellini) drain into the minor calyces
• Minor calyces → Major calyces → Renal pelvis → Ureter

Vascular Supply

• Cortical nephrons: efferent arteriole → peritubular capillaries (surround PCT and DCT)
• Juxtamedullary nephrons: efferent arteriole → vasa recta (long hairpin capillaries that descend into the medulla alongside the loop of Henle - critical for the countercurrent mechanism)

Lymphatics and Innervation

• Lymphatics drain to para-aortic nodes
• Innervation: sympathetic fibers via T8-L1 (renal plexus); no significant parasympathetic innervation
• Sympathetic activation → afferent arteriole constriction → ↓ GFR; also stimulates renin release and tubular Na⁺ reabsorption

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2. The Nephron - Functional Unit

Two Types of Nephrons

Parts of the Nephron (in order of filtrate flow)

1. Glomerulus + Bowman's capsule - filtration
2. Proximal convoluted tubule (PCT) - bulk reabsorption
3. Loop of Henle (descending thin limb → ascending thin limb → ascending thick limb) - countercurrent multiplier
4. Distal convoluted tubule (DCT) - fine-tuning of NaCl, Ca²⁺, Mg²⁺
5. Connecting tubule → Cortical collecting duct → Medullary collecting duct - final water/electrolyte regulation; site of ADH and aldosterone action

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3. The Glomerulus and Glomerular Filtration

Glomerular Structure

1. Fenestrated capillary endothelium (pores 70-100 nm): prevents cells from passing; pores covered by glycocalyx (negative charge)
2. Glomerular basement membrane (GBM) (Type IV collagen + heparan sulfate proteoglycans): primary barrier to proteins; negatively charged → repels albumin
3. Visceral epithelium (podocytes): foot processes with filtration slits (25-60 nm) bridged by the slit diaphragm (nephrin, podocin proteins) - main size barrier

• Freely permeable to: water, ions, glucose, amino acids, urea, creatinine, inulin
• Restricts: large proteins (albumin MW 69,000 Da is 0.04% filtered)
• Completely blocks: blood cells, large plasma proteins

Starling Forces at the Glomerulus (Net Filtration Pressure)

GFR - Normal Values and Regulation

• Normal GFR: 125 mL/min (180 L/day) in men; ~110 mL/min in women
• Urine output: only 1-2 L/day → 99% of filtered water is reabsorbed
• Filtered load = GFR × Plasma concentration

1. Myogenic mechanism: ↑ arterial pressure → afferent arteriole stretch → smooth muscle contracts → ↑ resistance → GFR stays constant
2. Tubuloglomerular feedback (TGF): ↑ GFR → ↑ NaCl delivery to macula densa (in the thick ascending limb where the DCT contacts the afferent arteriole) → macula densa releases adenosine → afferent arteriole constricts → ↓ GFR. This is mediated by the juxtaglomerular apparatus (JGA)

• Macula densa cells: NaCl-sensing cells in the thick ascending limb
• Juxtaglomerular (granular) cells: modified smooth muscle cells in the afferent arteriole; contain renin granules; act as baroreceptors
• Mesangial cells (extraglomerular)

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4. Tubular Transport - Segment by Segment

4a. Proximal Convoluted Tubule (PCT)

• Na⁺-K⁺-ATPase on the basolateral membrane pumps Na⁺ out of the cell, creating a low intracellular [Na⁺] and negative intracellular voltage (-70 mV)
• Na⁺ enters the cell from the tubular lumen down its electrochemical gradient via cotransporters and exchangers on the apical membrane

• 100% of glucose - via SGLT2 (90%) + SGLT1 (10%) on apical membrane; GLUT2/GLUT1 on basolateral
• 100% of amino acids - Na⁺-amino acid cotransporter
• ~85% of HCO₃⁻ - Na⁺/H⁺ exchanger (NHE3) secretes H⁺ → H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O (via carbonic anhydrase) → CO₂ enters cell → regenerated to HCO₃⁻
• 67% of Na⁺, Cl⁻, K⁺, water
• 50% of urea (passive)
• Phosphate, uric acid, organic acids

• Organic acids (urate, oxalate, bile salts)
• Drugs: penicillin, probenecid, methotrexate (via organic anion transporters, OAT)
• H⁺ (acid secretion)
• Creatinine (small amount)

4b. Proximal Tubule Transport Mechanism (Illustration)

4c. Loop of Henle

• Thin descending limb: highly permeable to water, less to solutes → water exits by osmosis as fluid descends into the hypertonic medulla → tubular fluid becomes concentrated (up to 1200 mOsm/L at the tip)
• Thin ascending limb: impermeable to water; some NaCl diffuses out passively
• Thick ascending limb (TAL): impermeable to water; actively pumps Na⁺, K⁺, 2Cl⁻ via NKCC2 cotransporter (furosemide target) → tubular fluid becomes dilute (~100 mOsm/L); this is the "diluting segment"

• Na⁺-K⁺-2Cl⁻ cotransporter: 1 Na⁺ + 1 K⁺ + 2 Cl⁻ into cell
• K⁺ recycles back through ROMK channels (into lumen) → generates a positive lumen potential → drives paracellular Ca²⁺ and Mg²⁺ reabsorption
• Loop diuretics (furosemide) block NKCC2 → massive Na⁺, K⁺, Cl⁻, Ca²⁺, Mg²⁺ loss in urine; abolish the medullary gradient → dilute urine even in the presence of ADH

4d. Distal Convoluted Tubule (DCT)

• Reabsorbs Na⁺, Cl⁻ via NCC (Na⁺-Cl⁻ cotransporter) - thiazide diuretic target
• Also reabsorbs Ca²⁺ (stimulated by PTH) and Mg²⁺
• Impermeable to water

• Apical: ENaC (epithelial Na⁺ channel) - aldosterone target; ROMK (K⁺ secretion)
• Basolateral: Na⁺-K⁺-ATPase
• Aldosterone ↑ ENaC and Na⁺-K⁺-ATPase synthesis → ↑ Na⁺ reabsorption + ↑ K⁺ secretion
• ADH (via V2 receptor → cAMP → AQP2 insertion) → ↑ water permeability

• Secrete H⁺ (via H⁺-ATPase and H⁺-K⁺-ATPase) into lumen
• Reabsorb K⁺ and HCO₃⁻
• Critical in metabolic acidosis (↑ H⁺ secretion)

• Secrete HCO₃⁻ into lumen; reabsorb H⁺
• Active in metabolic alkalosis

4e. Aldosterone Mechanism (Na⁺ Channel and Diuretic Sites)

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5. Urine Concentration and Dilution - The Countercurrent System

The Medullary Osmotic Gradient

1. Active NaCl transport by thick ascending limb (pumps solute without water into interstitium → hyperosmotic medulla)
2. Urea recycling: Urea is concentrated in the medullary collecting duct (permeable to urea via UT-A1/UT-A3 under ADH) → diffuses into inner medulla interstitium → some diffuses into thin ascending limb (UT-A2) → recycled
3. Countercurrent exchange by vasa recta: descending vasa recta gains solutes and loses water; ascending vasa recta loses solutes and gains water → prevents "washout" of the medullary gradient

ADH (Vasopressin) - The Master Switch

• ↑ plasma osmolarity (main stimulus - detected by hypothalamic osmoreceptors)
• ↓ blood volume/pressure (detected by cardiopulmonary and carotid baroreceptors)
• Nausea (very potent)
• Morphine, nicotine, stress

• ↓ plasma osmolarity
• ↑ blood volume
• Alcohol (→ diuresis)
• Clonidine, haloperidol

• Binds V2 receptors (Gs-coupled) on collecting duct principal cells
• → ↑ cAMP → PKA phosphorylates aquaporin-2 (AQP2)
• AQP2 vesicles insert into the apical membrane → ↑ water permeability
• Water moves from tubular lumen → hypertonic interstitium → vasa recta → concentrated urine

Tubular Fluid Osmolarity Along the Nephron

Table: Tubule Characteristics for Urine Concentration

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6. Renal Clearance - Measuring Kidney Function

Key Substances and Their Clinical Use

• Freely filtered, not reabsorbed or secreted → clearance = GFR exactly
• Not used clinically (requires IV infusion)

• Freely filtered, small amount secreted → slightly overestimates GFR by ~10-15%
• MDRD and CKD-EPI equations use serum creatinine to estimate GFR (eGFR)
• If GFR falls to 50% → plasma creatinine doubles (hyperbolic relationship)

• Filtered + secreted (90% extracted in one pass) → clearance ≈ renal plasma flow (~600 mL/min)
• Renal Blood Flow (RBF) = RPF / (1 - hematocrit) = 600 / 0.55 ≈ 1100 mL/min
• Filtration fraction (FF) = GFR/RPF = 125/600 = ~0.20 (20%)

• Clearance ratio < 1 (Cs/Cinulin < 1): substance is reabsorbed (glucose = 0 in normal person)
• Clearance ratio = 1: neither reabsorbed nor secreted (inulin)
• Clearance ratio > 1: substance is secreted (PAH, creatinine)

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7. Renin-Angiotensin-Aldosterone System (RAAS)

Stimulus for Renin Release (from JG cells):

1. ↓ afferent arteriole stretch (↓ BP)
2. ↓ NaCl delivery to macula densa
3. Sympathetic stimulation (β₁ receptors on JG cells)
4. Prostaglandins (PGE₂, PGI₂) stimulate renin

Cascade:

• Vasoconstriction (particularly efferent arteriole > afferent) → ↑ GFR maintained even in low CO
• Adrenal cortex (zona glomerulosa) → ↑ aldosterone secretion → ↑ Na⁺ reabsorption + K⁺ secretion in collecting duct
• Posterior pituitary → ↑ ADH release
• Hypothalamus → thirst
• Proximal tubule → ↑ Na⁺-H⁺ exchange → ↑ Na⁺ and HCO₃⁻ reabsorption
• Adrenal medulla → catecholamine release

Aldosterone (Mineralocorticoid):

• Produced in adrenal cortex zona glomerulosa
• Binds intracellular mineralocorticoid receptor → transcription of new proteins
• ↑ ENaC (apical) and Na⁺-K⁺-ATPase (basolateral) in principal cells
• Net effect: Na⁺ retained, K⁺ excreted, H₂O retained (follows Na⁺)
• Excess aldosterone (primary hyperaldosteronism/Conn's syndrome): hypertension, hypokalemia, metabolic alkalosis

Atrial Natriuretic Peptide (ANP):

• Released from cardiac atria when stretched (↑ volume)
• Antagonizes RAAS: dilates afferent arteriole + constricts efferent arteriole → ↑ GFR
• Inhibits renin, aldosterone, ADH release
• Direct inhibition of NaCl reabsorption in collecting duct
• Net: natriuresis (Na⁺ + water excretion) → ↓ volume

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8. Renal Acid-Base Regulation

1. Reabsorbing filtered HCO₃⁻ (85% in PCT)
2. Generating new HCO₃⁻ (titratable acids + NH₄⁺ excretion)
3. Secreting H⁺ into the urine

Bicarbonate Reabsorption (PCT - 85%):

• H⁺ secreted by NHE3 (Na⁺/H⁺ exchanger) into lumen
• H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O (via luminal carbonic anhydrase IV)
• CO₂ diffuses into cell → H₂CO₃ → H⁺ + HCO₃⁻ (via intracellular CA II)
• HCO₃⁻ exits basolateral membrane → blood
• Net: HCO₃⁻ "reclaimed" without being truly excreted

H⁺ Secretion and New HCO₃⁻ Generation (Collecting Duct):

• Type A intercalated cells: H⁺-ATPase and H⁺-K⁺-ATPase pump H⁺ into the lumen
• H⁺ buffered in urine by:
  • Phosphate (titratable acid): HPO₄²⁻ + H⁺ → H₂PO₄⁻
  • Ammonia buffer: NH₃ (produced from glutamine in PCT cells) + H⁺ → NH₄⁺ (trapped in urine)
  • NH₄⁺ excretion is the main mechanism for eliminating H⁺ in metabolic acidosis

Response to Acid-Base Disorders:

• Metabolic acidosis → ↑ H⁺ secretion, ↑ NH₄⁺ production, ↑ HCO₃⁻ generation
• Metabolic alkalosis → ↓ H⁺ secretion, ↑ HCO₃⁻ excretion (Type B intercalated cells secrete HCO₃⁻)
• Kidneys take hours to days to compensate (slower than lungs but more complete)

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9. Electrolyte Handling by the Kidney

Potassium (K⁺)

• Freely filtered; ~67% reabsorbed in PCT (passive)
• ~20% reabsorbed in thick ascending limb (via NKCC2)
• Secretion in principal cells of collecting duct = main determinant of K⁺ excretion
• Aldosterone ↑ K⁺ secretion
• High tubular flow rate ↑ K⁺ secretion (dilutes luminal K⁺)
• Alkalosis → K⁺ secretion ↑; Acidosis → K⁺ secretion ↓
• Clinical: Loop/thiazide diuretics → K⁺ loss (hypokalemia); K⁺-sparing diuretics (spironolactone, amiloride) → K⁺ retention

Calcium (Ca²⁺)

• ~60% filtered (40% protein-bound, not filtered)
• ~67% reabsorbed PCT (passive, paracellular)
• ~25% thick ascending limb (paracellular, driven by positive lumen potential via NKCC2)
• ~8% early DCT (active, via TRPV5 channels, stimulated by PTH)
• PTH → ↑ Ca²⁺ reabsorption in DCT and connecting tubule; ↑ 1,25-(OH)₂ vitamin D synthesis (stimulates intestinal absorption)
• Loop diuretics → ↓ Ca²⁺ reabsorption (used in hypercalcemia)
• Thiazides → ↑ Ca²⁺ reabsorption in DCT (used in hypercalciuria/calcium stones)

Phosphate (PO₄³⁻)

• ~80% reabsorbed in PCT via NaPi-IIa/IIc (Na⁺-phosphate cotransporter)
• PTH inhibits NaPi → ↑ phosphate excretion (phosphaturic effect)
• FGF-23 (from osteocytes) also inhibits NaPi; elevated in CKD → phosphate retention

Magnesium (Mg²⁺)

• ~25% reabsorbed PCT
• ~70% thick ascending limb (paracellular, driven by lumen positive potential)
• ~5% DCT
• Loop diuretics → Mg²⁺ loss (hypomagnesemia - common in ICU patients on furosemide)
• Hypomagnesemia causes refractory hypokalemia (impairs K⁺ reabsorption)

Urea

• Freely filtered; ~50% passively reabsorbed in PCT
• Secreted into thin ascending limb (recycling)
• ~40% of inner medullary interstitial osmolality is from urea
• BUN (blood urea nitrogen) rises in renal failure; BUN:Creatinine ratio:
  • Normal: 10:1 to 20:1

  • 20:1 → prerenal azotemia (↑ urea reabsorption with ↓ flow), upper GI bleed, protein catabolism

  • <10:1 → liver disease (↓ urea synthesis), protein malnutrition

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10. Pressure-Natriuresis and Long-Term Blood Pressure Control

1. ↑ MAP → ↑ renal perfusion pressure → ↑ GFR (minor)
2. ↑ MAP → ↓ renin, angiotensin II, aldosterone → ↓ tubular Na⁺ reabsorption
3. ↑ MAP → ↑ medullary blood flow → "washout" of medullary gradient → ↓ urine concentration → ↑ water excretion

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11. Clinical Correlations

11a. Staging of Chronic Kidney Disease (CKD)

• ↓ erythropoietin → normocytic anemia
• ↓ 1-α hydroxylase → ↓ active vitamin D (1,25-OH₂D₃) → hypocalcemia, secondary hyperparathyroidism → renal osteodystrophy
• ↑ phosphate retention → hyperphosphatemia (worsens hypocalcemia, calcification of vessels)
• ↑ BUN, creatinine → uremia (encephalopathy, pericarditis, nausea)
• ↓ H⁺ excretion → metabolic acidosis
• ↓ K⁺ excretion → hyperkalemia (life-threatening)
• Na⁺ and water retention → hypertension and edema

11b. Acute Kidney Injury (AKI) - Prerenal, Intrinsic, Postrenal

• <1%: tubules intact and avidly reabsorbing Na⁺ → prerenal or early obstruction
• >2%: tubular damage → ATN (can't reabsorb Na⁺)

11c. Glomerulonephritis (GN)

• Poststreptococcal GN: immune complex deposition (GBM); low complement; "lumpy-bumpy" pattern on IF; 2-4 weeks post-strep throat/skin infection
• IgA nephropathy (Berger disease): most common GN worldwide; mesangial IgA deposits; hematuria concurrent with URI; IgA visible on IF
• Rapidly Progressive GN (RPGN)/Crescentic GN: pauci-immune (ANCA+, e.g., Wegener's/GPA, MPA) or anti-GBM (Goodpasture's - linear IgG on IF + pulmonary hemorrhage)

• Minimal Change Disease (MCD): children; normal LM; effacement of podocyte foot processes on EM; responds to steroids
• Focal Segmental Glomerulosclerosis (FSGS): focal scarring; HIV, obesity, heroin; poor steroid response
• Membranous Nephropathy: thickened GBM, "spike and dome" pattern; subepithelial deposits; associated with PLA2R antibodies, hepatitis B, SLE, malignancy
• Diabetic Nephropathy: most common cause of CKD in developed world; Kimmelstiel-Wilson nodules (nodular glomerulosclerosis); microalbuminuria → macroalbuminuria → nephrotic syndrome

11d. Diuretics Summary

11e. Diabetes Insipidus (DI) vs SIADH

11f. Renal Tubular Acidosis (RTA) - "Normal Anion Gap Metabolic Acidosis"

11g. RAAS Blockade - Clinical Applications

• ACE inhibitors / ARBs: dilate efferent arteriole → ↓ glomerular pressure → renoprotective in diabetic and hypertensive nephropathy; reduce proteinuria; can cause acute AKI in bilateral renal artery stenosis (remove the efferent constriction maintaining GFR)
• SGLT2 inhibitors (empagliflozin, dapagliflozin): block SGLT2 in PCT → glucosuria + natriuresis; reduce intraglomerular pressure via tubuloglomerular feedback; strongly renoprotective in CKD + DM2; also reduce cardiovascular mortality
• MRA (spironolactone, finerenone): block mineralocorticoid receptor in collecting duct; renoprotective in CKD + DM; ↑ K⁺ (monitor)

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12. Key Normal Values to Remember

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Sources

• Guyton and Hall Textbook of Medical Physiology (14th ed.) - Chapters 26-32
• Costanzo Physiology (7th ed.) - Chapter 6
• Brenner and Rector's The Kidney (11th ed.)
• Comprehensive Clinical Nephrology (7th ed.)
• Tietz Textbook of Laboratory Medicine (7th ed.)

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Cardiology: Anatomy, Physiology, and Clinicals

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1. Cardiac Anatomy

Gross Structure

• Right atrium (RA): receives deoxygenated blood from superior vena cava (SVC), inferior vena cava (IVC), and coronary sinus; contains the SA node and Eustachian valve (vestigial)
• Right ventricle (RV): pumps to pulmonary circulation (low pressure ~25/8 mmHg); crescent-shaped cross section; thinner walls than LV
• Left atrium (LA): receives oxygenated blood from 4 pulmonary veins; contains the fossa ovalis on interatrial septum (remnant of foramen ovale)
• Left ventricle (LV): pumps to systemic circulation (high pressure ~120/80 mmHg); elliptical, thick-walled (8-12 mm); contains papillary muscles and trabeculae carnae

Heart Valves

Coronary Circulation

• Originates from right coronary sinus of aorta
• Supplies: RA, RV, SA node (~60%), AV node (~90%), inferior LV
• Branches: posterior descending artery (PDA) in right-dominant circulation (~85% of people) - supplies inferior wall and posterior interventricular septum

• Short main (left main ~1-2 cm) then divides into:
• Left anterior descending (LAD): supplies anterior LV, anterior 2/3 of interventricular septum, anterior papillary muscle, apex. "Artery of widowmaker"
• Left circumflex (LCx): supplies lateral and posterior LV wall; SA node (~40%); in left-dominant systems, gives PDA

• ~250 mL/min at rest (~5% of cardiac output)
• Occurs mainly in diastole (LV compresses coronary arteries during systole)
• Autoregulated (metabolic: ↑ adenosine, NO when O₂ demand ↑)
• Subendocardium is most vulnerable to ischemia (lowest perfusion pressure, most wall stress)

Layers of the Heart Wall

• Epicardium: outer visceral pericardium; contains coronary arteries and fat
• Myocardium: cardiac muscle; the working layer
• Endocardium: inner lining; smooth endothelial surface; includes Purkinje fibers

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2. Cardiac Electrophysiology

The Conduction System

1. Action potential originates in SA node
2. Rate 60-100 beats/min
3. Activation sequence and timing are correct

• SA node: 60-100/min (dominant pacemaker)
• AV node / His: 40-60/min
• Bundle branches / Purkinje: 20-40/min
• Ventricular myocardium: <20/min

• Atrial myocardium: 1 m/s
• AV node: 0.05 m/s (slowest - creates the PR interval delay for ventricular filling)
• His-Purkinje system: 4 m/s (fastest - ensures near-simultaneous ventricular activation)
• Ventricular myocardium: 1 m/s

Ventricular Action Potential - Phases

SA Node Action Potential (Pacemaker Potential)

• No stable phase 4 - instead has a spontaneous "funny current" (If, inward Na⁺/K⁺ current) that causes slow diastolic depolarization until threshold is reached → spontaneous firing = automaticity
• Phase 0 upstroke driven by slow Ca²⁺ channels (ICa-L), not fast Na⁺ channels
• No true plateau
• Resting membrane potential: ≈ -55 to -60 mV (less negative than ventricle)
• Ivabradine (heart rate drug) specifically blocks If channels in SA node

Autonomic Effects on the Heart

• L-type Ca²⁺ channel → ↑ Ca²⁺ entry
• Phospholamban (removes inhibition of SERCA2) → faster SR Ca²⁺ uptake → faster relaxation (lusitropy)
• Troponin I → reduces Ca²⁺ sensitivity of myofibrils → faster cross-bridge cycling

Excitation-Contraction Coupling (E-C Coupling)

1. Action potential → depolarization of T-tubule membrane
2. L-type Ca²⁺ channels (DHP receptors) open → small Ca²⁺ influx ("trigger Ca²⁺")
3. Trigger Ca²⁺ activates ryanodine receptors (RyR2) on sarcoplasmic reticulum → Ca²⁺-induced Ca²⁺ release (CICR) → large Ca²⁺ release into cytosol
4. [Ca²⁺]i rises from 0.1 µM → ~1 µM → binds troponin C → conformational change → tropomyosin moves off actin binding sites
5. Myosin heads bind actin → cross-bridge cycling → contraction
6. Relaxation: Ca²⁺ removed by SERCA2 (back to SR), NCX (Na⁺/Ca²⁺ exchanger, extrudes Ca²⁺), and plasma membrane Ca²⁺-ATPase

• Absolute refractory period (ARP): No stimulus can trigger another AP (Na⁺ channels inactivated). Corresponds roughly to systole - prevents tetanus (essential for cardiac function)
• Relative refractory period (RRP): Above-threshold stimulus can trigger AP (partial Na⁺ channel recovery). Corresponds to early diastole - vulnerable to "R-on-T" phenomenon → VF

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3. The Cardiac Cycle

Full Cycle - 7 Phases (at HR 75 bpm → cycle duration ~0.8 sec)

• LV systolic pressure: ~120 mmHg
• LV end-diastolic pressure (LVEDP): 5-12 mmHg (↑ in LV failure, mitral stenosis)
• Aortic systolic: ~120 mmHg; diastolic: ~80 mmHg
• Pulse pressure = systolic - diastolic = 40 mmHg (↑ in aortic regurgitation, ↓ in tamponade/severe AS)

Atrial Pressure Waves (a, c, v)

• a wave: atrial contraction (follows P wave)
• c wave: AV valve closure bulging back into atrium (small)
• v wave: venous filling of atrium while AV valve is closed (follows T wave)
• Cannon a waves: giant a waves when RA contracts against closed tricuspid valve → seen in complete AV block, VT
• Absent a wave: atrial fibrillation (no organized atrial contraction)

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4. Key Hemodynamic Parameters

Volumes

• End-Diastolic Volume (EDV): ~120-130 mL (volume of blood in LV at end of diastole = preload)
• End-Systolic Volume (ESV): ~50-60 mL (blood remaining after ejection)
• Stroke Volume (SV) = EDV - ESV = 70 mL (range 60-100 mL)
• Ejection Fraction (EF) = SV/EDV = 70/130 = ~55-65% (normal ≥55%)
  • EF <40% = reduced EF (HFrEF)
  • EF 41-49% = mildly reduced (HFmrEF)
  • EF ≥50% = preserved (HFpEF if symptoms present)
• Cardiac Output (CO) = SV × HR = 70 mL × 75 bpm = ~5 L/min
• Cardiac Index (CI) = CO/BSA = ~3 L/min/m² (normal >2.2 L/min/m²)

Determinants of Cardiac Output

• ↑ Preload → ↑ sarcomere stretch → ↑ SV (Frank-Starling)
• Increased by: ↑ venous return, bradycardia, exercise (venous pump), regurgitant lesions

• ↑ Afterload → ↓ SV (failing heart more sensitive)
• Increased by: hypertension, aortic stenosis, vasoconstriction
• Decreased by: vasodilators (ACE inhibitors) → ↑ SV in heart failure

• ↑ by: catecholamines, digoxin, ↑ heart rate (Bowditch/staircase), digitalis
• ↓ by: heart failure, acidosis, hypoxia, β-blockers (acutely), Ca²⁺ channel blockers

• ↑ HR → ↑ CO (to a point; >150-180 bpm → ↓ filling time → ↓ SV may offset)
• HR determined by SA node, modulated by ANS and baroreceptors

Frank-Starling Mechanism

• More filling → greater stretch → more Ca²⁺ sensitivity of troponin C + more Ca²⁺ release from SR → stronger contraction → ↑ SV
• Heart automatically matches output to venous return without neural input
• Clinical: fluid bolus in sepsis → ↑ preload → ↑ CO (if on ascending limb); in HF, curve shifts downward (less SV at same preload)

Cardiac and Vascular Function Curves

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5. ECG Basics

Intervals and Waves

• Left axis deviation (LAD): left anterior fascicular block, inferior MI
• Right axis deviation (RAD): RVH, left posterior fascicular block, lateral MI

Key ECG Patterns

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6. Antiarrhythmic Drugs - Vaughan Williams Classification

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7. Heart Failure (HF)

Definition and Pathophysiology

• HFrEF (EF <40%): reduced contractility; dilated cardiomyopathy pattern; systolic dysfunction
• HFpEF (EF ≥50%): impaired relaxation/filling; concentric hypertrophy; diastolic dysfunction; EF normal but SV reduced due to ↓ EDV

Compensatory Mechanisms (initially helpful, ultimately harmful)

1. Frank-Starling: ↑ EDV → ↑ SV (works until excessive dilation → ↓ efficiency)
2. Neurohormonal activation: RAAS ↑ → Na⁺/water retention; SNS ↑ → ↑ HR, vasoconstriction; ADH ↑ → water retention → all raise preload + afterload (vicious cycle)
3. Cardiac hypertrophy: initially reduces wall stress (LaPlace), but → fibrosis, ↓ compliance, arrhythmias
4. Natriuretic peptides (ANP/BNP): secreted from atria/ventricles in response to stretch → natriuresis, vasodilation, ↓ renin (counterregulatory; useful as biomarkers)

Clinical Presentation

• Left HF (elevated pulmonary venous pressure): dyspnea on exertion, orthopnea, PND (paroxysmal nocturnal dyspnea), pulmonary crackles, S3 gallop, ↑ PCWP
• Right HF (elevated systemic venous pressure): JVD, peripheral edema, hepatomegaly, ascites, ↑ RAP
• Biventricular HF: features of both; most common (LHF → ↑ pulmonary pressure → RHF)

• Major: PND, JVD, crackles, cardiomegaly, S3, ↑ CVP, pulmonary edema
• Minor: bilateral ankle edema, nocturnal cough, dyspnea on exertion, hepatomegaly, tachycardia

NYHA Functional Classification

ACC/AHA Stages of HF

Treatment of HFrEF (The "Fantastic Four")

1. ACE inhibitor/ARB (or ARNI - sacubitril/valsartan, preferred over ACEi): ↓ afterload, ↓ remodeling, ↓ neurohormonal activation; 20-40% mortality reduction
2. β-blocker (carvedilol, metoprolol succinate, bisoprolol): ↓ HR, ↑ filling time, ↓ remodeling, antiarrhythmic; ~34% mortality reduction
3. MRA (mineralocorticoid receptor antagonist): spironolactone, eplerenone; ↓ aldosterone effect → ↓ fibrosis, ↓ remodeling
4. SGLT2 inhibitors (dapagliflozin, empagliflozin): ↓ HF hospitalizations and mortality regardless of EF; also in HFpEF (dapagliflozin)

• Diuretics (loop diuretics - furosemide): symptom relief, ↓ congestion; do NOT reduce mortality
• ICD: EF ≤35%, NYHA II-III, >40 days post-MI - prevents sudden cardiac death
• CRT (cardiac resynchronization therapy): EF ≤35% + LBBB (QRS ≥150 ms) - improves CO by synchronizing LV contraction
• Ivabradine: HR >70, sinus rhythm on max β-blocker - reduces HF hospitalizations

Clinical Case in Point (Costanzo)

• ↓ Contractility → downward shift of Frank-Starling curve → ↓ SV at same preload
• Baroreceptor activation → ↑ SNS (tachycardia, vasoconstriction, cold clammy skin)
• RAAS activation → Na⁺/water retention → worsening edema
• Treatment: digoxin (↑ contractility), diuretic + low Na diet (↓ volume overload)

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8. Arrhythmias

Mechanisms of Arrhythmias

1. Abnormal automaticity: ectopic pacemaker fires faster than SA node; seen in hypokalemia, ischemia, catecholamine excess
2. Triggered activity: after-depolarizations
   • Early after-depolarizations (EADs): during phase 2-3 (prolonged QT) → Torsades de pointes
   • Delayed after-depolarizations (DADs): after phase 4 (digoxin toxicity, catecholamine excess)
3. Re-entry: most common mechanism; requires two pathways with unidirectional block and different conduction velocities → circular excitation loop; substrate for AF, VT, SVT

Classification of Major Arrhythmias

• Most common sustained arrhythmia; prevalence increases with age (10% in >80 yr)
• Multiple disorganized re-entrant wavelets in atria; usually triggered from pulmonary veins
• ECG: irregularly irregular rhythm, absent P waves, fibrillatory baseline, narrow QRS (unless aberrant conduction)
• Risks: stroke (LA thrombus from blood stasis, especially in LAA), HF (tachycardia-induced cardiomyopathy)
• CHA₂DS₂-VASc score for stroke risk → anticoagulation with DOACs (apixaban, rivaroxaban, dabigatran) if score ≥2 (male) or ≥3 (female)
• Management: rate control (β-blockers, diltiazem/verapamil, digoxin) vs. rhythm control (cardioversion, antiarrhythmics, catheter ablation - PVI)

• Organized macro-re-entry circuit in right atrium (typical - counterclockwise around tricuspid annulus)
• ECG: sawtooth P waves at ~300/min; usually 2:1 block → ventricular rate ~150/min
• Same stroke risk as AF → anticoagulation strategy similar
• Often easier to convert; catheter ablation highly effective (>90% cure rate for typical flutter)

• Most common SVT; re-entry within AV node using slow and fast pathways
• Rate 150-250/min; narrow QRS; P waves buried in or just after QRS
• Vagal maneuvers or adenosine terminate acutely
• Long-term: β-blockers, CCBs, or catheter ablation

• Accessory pathway (bundle of Kent) bypasses AV node → ventricular preexcitation
• ECG: short PR (<0.12 s) + delta wave + wide QRS
• Can conduct AF very rapidly through accessory pathway → hemodynamic collapse/VF
• Contraindication: AV nodal blockers (adenosine, digoxin, CCBs) in AF with WPW → accelerate AP conduction → VF
• Treatment: procainamide acutely; catheter ablation for definitive cure

• ≥3 consecutive ventricular beats at ≥100/min; wide QRS (>0.12 s)
• Sustained VT (>30 sec or hemodynamically unstable): immediate cardioversion
• Monomorphic VT: usually scar-based re-entry (post-MI, cardiomyopathy)
• Polymorphic VT: ischemia, electrolyte abnormalities

• Chaotic, uncoordinated ventricular activity; no effective cardiac output → cardiac arrest
• Treatment: immediate defibrillation + CPR; amiodarone/lidocaine during resuscitation

• Polymorphic VT with QRS that twists around the isoelectric line
• Occurs in setting of prolonged QT interval
• Causes: drugs (class IA, III, QT-prolonging antibiotics/antipsychotics), hypokalemia, hypomagnesemia, congenital LQTS
• Treatment: IV magnesium sulfate (first-line); overdrive pacing; correct electrolytes; remove offending drug

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9. Ischemic Heart Disease

Stable Angina

• Demand > supply ischemia (fixed atherosclerotic stenosis)
• Exertional chest pain, relieved by rest or nitrates in <10 min
• ECG: may show ST depression during pain; normal at rest
• Management:
  • Short-acting nitrates (GTN) - symptom relief
  • β-blockers (↓ HR and contractility → ↓ O₂ demand) - first-line
  • Long-acting nitrates, Ca²⁺ channel blockers as add-on
  • Statins, aspirin, lifestyle modification
  • Revascularization: PCI or CABG for severe/refractory disease

Acute Coronary Syndrome (ACS)

• Primary PCI (percutaneous coronary intervention) within 90 min of first medical contact (preferred)
• Thrombolysis if PCI not available within 120 min
• Aspirin + P2Y12 inhibitor (clopidogrel, ticagrelor, prasugrel) = dual antiplatelet therapy (DAPT)
• Anticoagulation: heparin (UFH or LMWH), fondaparinux, bivalirudin
• β-blockers (↓ infarct size, ↓ arrhythmias)
• ACE inhibitors (↓ remodeling)
• Statin (high-intensity)

• Arrhythmias: most common early cause of death; VF (first 24-48 hrs - reperfusion); heart block (inferior MI → RCA occlusion → AV node ischemia)
• Pump failure/Cardiogenic shock: massive LV infarct (>40% of LV mass); Killip Class IV; mortality >50%; treatment: IABP, revascularization
• Mechanical complications (day 3-7: "3-7 days"):
  • Free wall rupture → hemopericardium → cardiac tamponade → death
  • Papillary muscle rupture → acute severe mitral regurgitation → pulmonary edema (new systolic murmur + respiratory failure)
  • VSD (interventricular septal rupture) → new systolic murmur + ↑ O₂ saturation in RV (step-up)
• LV aneurysm: persistent ST elevation, ventricular tachyarrhythmias, mural thrombus → stroke
• Pericarditis: Dressler's syndrome (autoimmune, days to weeks post-MI); fever, pleuritic chest pain, friction rub

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10. Valvular Heart Disease

Overview

• Most common valvular abnormality in developed countries (~2-3% of population)
• Myxomatous degeneration of mitral leaflets → prolapse into LA during systole
• Mid-systolic click followed by late systolic murmur
• Mostly benign; rarely causes significant MR or arrhythmias

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11. Pericardial Diseases

Acute Pericarditis

• Sharp pleuritic chest pain; worse lying flat, better sitting forward
• Pericardial friction rub (pathognomonic) - scratchy, 3-component sound
• ECG: diffuse saddle-shaped ST elevation + PR depression (contrast with MI: regional ST elevation without PR depression)
• Causes: viral (most common - Coxsackie, Echo), post-MI (Dressler's), autoimmune (SLE, RA), uremic, TB
• Treatment: NSAIDs + colchicine (reduces recurrence)

Cardiac Tamponade

• Fluid accumulation in pericardial space → ↑ intrapericardial pressure → compression of cardiac chambers
• Beck's Triad: hypotension + JVD + muffled heart sounds
• Pulsus paradoxus: ↓ SBP >10 mmHg during inspiration (normal ≤10 mmHg) - due to exaggerated ventricular interdependence
• ECG: electrical alternans (QRS axis alternates beat-to-beat), low voltage, tachycardia
• Echo: right-sided chamber diastolic collapse, plethoric IVC
• Treatment: pericardiocentesis (emergency)

Constrictive Pericarditis

• Rigid, fibrotic pericardium → impairs cardiac filling in diastole
• Causes: post-TB (most common worldwide), radiation, post-viral, post-surgical
• JVD with Kussmaul sign (JVD increases on inspiration - opposite of normal)
• Pericardial knock (high-pitched S3-like sound)
• Equalization of diastolic pressures in all 4 chambers
• Treatment: pericardiectomy

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12. Hypertension

• Primary (essential) HTN (95%): no identified cause; genetic + environmental (high Na, obesity, sedentary, alcohol)
• Secondary HTN (5%): renovascular (RAS), primary hyperaldosteronism, pheochromocytoma, obstructive sleep apnea, thyroid disease, coarctation of aorta

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13. Key Normal Hemodynamic Values

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Sources

• Guyton and Hall Textbook of Medical Physiology (14th ed.) - Chapters 9-13, 20-21
• Costanzo Physiology (7th ed.) - Chapter 4
• Goldman-Cecil Medicine (International Ed.) - Chapters 45-58
• Braunwald's Heart Disease (12th ed.)
• Harrison's Principles of Internal Medicine (22nd ed.) - Chapters 251-256

ECG - From Basics to Clinicals

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1. The ECG Signal: What We're Actually Recording

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2. ECG Paper and Calibration

• Horizontal (time): 1 small box = 1 mm = 40 ms; 1 large box (5 small) = 200 ms
• Vertical (voltage): Standard calibration = 10 mm = 1 mV

• HR (bpm) = 300 ÷ number of large boxes between R waves (for regular rhythms)
• Or: count R waves in a 10-second strip × 6
• Or: 1500 ÷ number of small boxes between R-R intervals

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3. The 12-Lead System

Limb Leads (Frontal Plane)

Precordial Leads (Horizontal Plane)

• Right-sided leads (V3R-V6R): Detect right ventricular MI - always get V3R/V4R in inferior STEMI
• Posterior leads (V7-V9): Detect posterior MI (ST elevation posterior = ST depression in V1-V3)

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4. Normal ECG Waveforms and Intervals

Waveform Descriptions

• Duration: < 120 ms; Amplitude: < 2.5 mm
• Normal: upright in I, II, aVF, V4-V6; inverted in aVR
• Represents atrial depolarization (right then left atrium)
• Sinus P waves: always positive in II, always negative in aVR

• Normal: 120-200 ms (3-5 small boxes)
• Measured from start of P to start of QRS
• Represents conduction through: atria → AV node → His bundle → bundle branches → Purkinje

• Normal: ≤ 100-110 ms (≤ 2.5 small boxes)
• Naming: first negative = Q, first positive = R, negative after R = S, second positive = R'
• If entirely negative = QS complex

• Normal septal Q waves: < 40 ms wide, < 25% of R-wave amplitude, in I, aVL, V5, V6
• Pathologic Q waves: ≥ 40 ms wide OR ≥ 25% R amplitude → indicate prior infarction

• Measured from J-point (QRS-ST junction) to start of T wave
• Normal: isoelectric (< 1 mm deviation in limb leads, < 2 mm in precordial)

• Normally concordant (same direction) with QRS
• Normally upright in I, II, V2-V6; inverted in aVR (normal)
• Normally inverted in V1 (and sometimes V2-V3 in women)

• Measured from start of QRS to end of T wave
• Rate-corrected (QTc): QT ÷ √RR (Bazett formula, units in seconds)
• Framingham: QTc = QT + 0.154(1000 - RR) in ms - more accurate at extremes
• Normal QTc: ≤ 450 ms (men), ≤ 460 ms (women)

• Small, rounded, follows T wave, < 1 mm, same polarity as T
• Prominent U wave → hypokalemia, bradycardia, drugs (amiodarone, sotalol, dofetilide)

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5. Normal Sinus Rhythm - Criteria

1. P waves present and regular
2. P wave positive in lead II, negative in aVR (confirming sinus origin)
3. Every P wave followed by a QRS (1:1 P:QRS ratio)
4. PR interval 120-200 ms and constant
5. Rate 60-100 bpm
6. Regular R-R intervals (variation < 10%, or up to 12% with respiratory variation)

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6. The Normal 12-Lead ECG

Normal R-Wave Progression

• V1: small r, deep S (rS pattern) - right precordial, septal depolarization moves away
• V2-V3: transitional - increasing R
• Transition zone (R = S): normally V3 or V4
• V5-V6: tall R, small s (Rs or R pattern) - left precordial, LV dominates

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7. Cardiac Axis

Hexaxial Reference System

Quick Axis Determination

Causes of Axis Deviation

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8. Normal Ventricular Depolarization - The Two Vectors

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9. Cardiac Hypertrophy Patterns

Left Ventricular Hypertrophy (LVH)

• Sokolow-Lyon: SV1 + RV5 (or V6) ≥ 35 mm
• Cornell: RaVL + SV3 > 28 mm (men) or > 20 mm (women)
• RaVL > 20 mm (women) or > 28 mm (men) alone

• ST depression + T-wave inversion (asymmetric) in leads with prominent R waves (I, aVL, V5-V6)
• Indicates pressure or volume overload, worsens prognosis

• Left atrial abnormality (broad, notched P in II; biphasic P in V1)
• LAD (left axis deviation, sometimes)

Right Ventricular Hypertrophy (RVH)

• R ≥ S in V1 (dominant R wave in right precordial leads) - the key finding
• Right axis deviation (> +90°) - usually present
• rSR' pattern in V1 (similar to RBBB but QRS < 120 ms with incomplete RBBB)
• ST depression and T-wave inversions in V1-V3 ("RV strain")
• Prominent S waves in V5-V6 (qRS or RS pattern)
• qR pattern in V1 suggests severe RVH

• S1Q3T3 pattern - S wave in I, Q wave in III, T-wave inversion in III (not specific, but classic)
• Sinus tachycardia, right bundle branch block, RV strain

Atrial Abnormalities

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10. Bundle Branch Blocks

Right Bundle Branch Block (RBBB)

• QRS ≥ 120 ms (complete); 110-120 ms (incomplete)
• rSR' ("rabbit ears") in V1 or V2 - the hallmark
• Wide, slurred S waves in I, aVL, V5-V6
• Secondary T-wave inversion in V1-V2 (opposite to terminal R')

Left Bundle Branch Block (LBBB)

• QRS ≥ 120 ms (complete)
• Broad, notched R wave in I, aVL, V5-V6 (no q waves in these leads)
• QS or rS complex in V1 - the hallmark right precordial pattern
• Discordant ST-T: T waves opposite to dominant QRS deflection (ST elevation in V1-V2, ST depression in V5-V6)

• Often indicates underlying heart disease: CAD (most common), hypertensive heart disease, aortic valve disease, cardiomyopathy
• New LBBB in chest pain = STEMI-equivalent (Sgarbossa criteria below)
• Masks LVH and inferior MI on ECG
• Indication for CRT if QRS ≥ 130-150 ms + HFrEF + NYHA II-IV

Sgarbossa Criteria for MI in LBBB

Fascicular Blocks (Hemiblocks)

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11. Ischemia and Infarction Patterns

Mechanism of ST Changes

The Evolutionary ECG Changes of STEMI

Minutes:          "Hyperacute" tall, peaked T waves (earliest - often missed)
                         ↓
Hours:            ST elevation (tombstone shape) with tall T
                         ↓
Hours-days:       ST elevation + Q waves develop + T-wave inversion begins
                         ↓
Days-weeks:       Q waves persist, ST resolves, deep T-wave inversions
                         ↓
Months-years:     Q waves remain (permanent scar marker), T waves may normalize

Localizing the Infarct Territory

1. V3R/V4R for RV involvement (ST elevation > 0.5 mm → RV infarct → avoid nitrates and diuretics)
2. V1-V3 for ST depression (posterior involvement → add posterior leads)
3. ST elevation in III > II suggests RCA; ST elevation in II ≥ III + ST depression in V1-V3 suggests LCx (circumflex)

Q-Wave Patterns

• Transmural MI can occur without Q waves ("non-Q-wave MI")
• Subendocardial MI can develop Q waves
• Preferred terms: "Q-wave MI" vs "non-Q-wave MI" rather than transmural vs subendocardial

• LBBB (QS in V1-V2)
• WPW (delta wave may mimic Q)
• HCM (septal hypertrophy → deep narrow Q in I, aVL, V5-V6)
• RVH (QR pattern in V1)
• COPD (QS in V1-V3)

Wellens Syndrome

• Type A: Biphasic T waves (positive-negative) in V2-V3
• Type B: Deep symmetric T inversions in V2-V3 (more common)

De Winter Pattern

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12. QT Prolongation and Torsades de Pointes

QTc Normal Values

Causes of QT Prolongation

• Class IA antiarrhythmics: quinidine, procainamide, disopyramide
• Class III antiarrhythmics: amiodarone (usually modest), sotalol, dofetilide, ibutilide
• Antibiotics: azithromycin, fluoroquinolones, erythromycin
• Antifungals: fluconazole
• Antipsychotics: haloperidol, quetiapine, ziprasidone
• Antidepressants: TCA, SSRIs (citalopram)
• Antiemetics: ondansetron, metoclopramide

• LQT1 (KCNQ1/IKs): broad T wave, events with exercise (swimming) - β-blocker therapy
• LQT2 (KCNH2/IKr = HERG): notched T wave, events with sudden noise - avoid QT-prolonging drugs
• LQT3 (SCN5A/INa): late-onset long isoelectric ST, events at rest/sleep - mexiletine, ICD

• Polymorphic VT with QRS complexes that twist around the isoelectric line
• Associated with QTc > 500 ms
• Typically self-limiting but can degenerate to VF
• Treatment: IV magnesium sulfate (2 g IV bolus) → cardiac pacing to increase rate (shorten QT) → avoid QT-prolonging drugs → correct electrolytes

Short QT Syndrome

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13. Electrolyte Effects on the ECG

Hyperkalemia - Progressive Sequence

1. Calcium gluconate (membrane stabilization, immediate) - does NOT lower K+
2. Insulin + glucose (shift K+ intracellularly - 15-30 min onset)
3. Sodium bicarbonate (alkalosis shifts K+ in)
4. Kayexalate / patiromer / sodium zirconium cyclosilicate (eliminate K+)
5. Dialysis (severe/refractory)

Hypokalemia

• Flattened T waves + prominent U waves (T-U fusion giving appearance of "prolonged QT")
• True QT may not be as prolonged as it appears if U wave is merged with T
• ST depression
• Increases arrhythmia risk; potentiates digoxin toxicity

Hypocalcemia

• Prolonged QT interval (specifically prolongs the ST segment / phase 2)
• Mild T-wave changes

Hypercalcemia

• Short QT interval (shortens phase 2)
• Osborn (J) waves may occasionally be seen
• Can cause bradycardia and AV block at very high levels

Hypothermia (< 35°C)

• Osborn (J) waves: Positive deflection at the J-point (QRS-ST junction), most prominent in inferior and lateral leads - pathognomonic of hypothermia
• Bradycardia, prolonged PR, QRS, and QT
• Tremor artifact (muscle shivering)

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14. AV Conduction Abnormalities (Heart Blocks)

First-Degree AV Block

• PR interval > 200 ms (> 1 large box)
• Every P followed by QRS (1:1 conduction, just slow)
• Usually benign; can be due to vagal tone, digoxin, beta-blockers, calcium channel blockers, AV node disease

Second-Degree AV Block

• Progressive PR prolongation until a P wave is not conducted (dropped QRS)
• Then cycle resets
• The PR after the dropped beat is the shortest; the PR before the dropped beat is the longest
• Usually at the AV node level (responds to atropine)
• Often reversible (inferior MI, vagal excess, drugs)
• Usually benign - rarely needs pacing unless symptomatic

• Constant PR interval with sudden, unexpected dropped QRS (no warning PR lengthening)
• Located below the AV node (His-Purkinje system)
• High risk of progression to complete (3rd-degree) heart block
• Usually requires pacing even if asymptomatic

• Every other P is conducted - cannot determine Mobitz type by PR criterion alone
• Look at QRS width: narrow QRS = likely Wenckebach (nodal); wide QRS = likely Mobitz II (infranodal)
• Also look at response to exercise/atropine: if conduction improves → nodal; if worsens → infranodal

• 2 or more consecutive non-conducted P waves
• Essentially impending complete block → pacing

Third-Degree (Complete) AV Block

• Complete AV dissociation - no relationship between P waves and QRS complexes
• P-P interval regular; R-R interval regular; but completely independent
• Escape rhythm: Junctional (narrow QRS, 40-60 bpm, usually stable) or ventricular (wide QRS, 20-40 bpm, unstable)
• Emergency pacing indicated
• Causes: inferior MI (often reversible - junctional escape, responds to atropine), anterior MI (usually permanent - wide QRS escape), Lyme disease, digoxin toxicity, surgical complication, idiopathic calcific degeneration

AV Dissociation vs Complete Heart Block

• AV dissociation: two independent pacemakers (ventricular rate ≥ atrial rate) - does NOT require pacing
• Complete heart block: atrial rate > ventricular rate, with no conduction - usually requires pacing

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15. Pre-excitation: WPW Syndrome

1. Short PR interval (< 120 ms) - no AV nodal delay
2. Delta wave - slurred upstroke to QRS (fusion of pre-excited and normally conducted activation)
3. Wide QRS (> 120 ms, delta wave contribution)

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16. ST-T Wave Abnormalities: Differential

ST Elevation - Differential Diagnosis

ST Depression - Differential

T-Wave Inversion - Differential

• Ischemia/evolving MI: V1-V4 (anterior) or II/III/aVF (inferior)
• Wellens pattern: Deep symmetric V2-V3 = proximal LAD disease
• RVH strain: V1-V3 with right axis deviation
• RBBB: Secondary T-wave inversions in V1-V2 (normal and expected)
• LBBB: Secondary T-wave inversions in I, V5-V6 (opposite to QRS, normal in LBBB)
• PE (acute cor pulmonale): T inversions V1-V4 + S1Q3T3
• CNS events (subarachnoid hemorrhage): "CVA T waves" - deep, wide, diffuse inversions, long QT
• Hypertrophic cardiomyopathy: Deep T-wave inversions (can be very dramatic, especially in apical HCM)
• Takotsubo: Deep T inversions post-event in precordial leads
• Cardiac memory: T inversions after resolution of LBBB or ventricular pacing

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17. The Brugada Pattern/Syndrome

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18. Key ECG Intervals - Normal Values Summary

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19. Systematic Approach to ECG Interpretation

1. Rate: Calculate atrial and ventricular rates (may differ in heart block)
2. Rhythm: Regular or irregular? If irregular: regularly irregular (Wenckebach, bigeminy) or irregularly irregular (AF)?
3. P waves: Present? Morphology normal? Every P followed by QRS?
4. PR interval: 120-200 ms? Constant? Progressive? Missing?
5. QRS duration: Normal (< 110 ms) or wide (≥ 120 ms)?
6. Axis: I and aVF positive = normal; LAD or RAD?
7. Hypertrophy: LVH voltage criteria? Atrial abnormalities?
8. QRST morphology: Q waves (location, size)? ST elevation/depression? T-wave changes?
9. QT interval: Calculate QTc; > 500 ms = danger zone
10. Clinical correlation: Integrate with the patient's presentation

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20. Drug Effects on the ECG

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Key Values Quick-Reference

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What Was Covered in the ECG Response

• ECG signal origin - cellular action potential mapping to P-QRS-T (with Harrison's diagram showing ionic currents per region)
• ECG paper calibration (25 mm/s, 10 mm/mV)
• Heart rate calculation methods

• All 6 limb leads and 6 precordial leads (positions, angles, what each "sees")
• Additional leads: right-sided (V3R/V4R for RV infarct), posterior (V7-V9)

• P wave, PR interval, QRS, ST segment, T wave, U wave, QT/QTc
• Normal values table; Bazett and Framingham QTc formulas

• Quick 4-quadrant method using leads I and aVF
• Causes of LAD and RAD

• Normal R-wave progression; transition zone V3-V4

• LVH: Sokolow-Lyon, Cornell voltage criteria; strain pattern
• RVH: dominant R in V1, RAD, RV strain
• Atrial abnormalities: P-pulmonale, P-mitrale

• RBBB: rSR' in V1, wide S in I/V6
• LBBB: QS in V1, broad R in V6; Sgarbossa criteria for MI in LBBB
• LAFB and LPFB (fascicular blocks)
• Bifascicular and trifascicular block

• Mechanism of ST changes (current of injury diagram)
• STEMI evolutionary sequence (hyperacute T → ST elevation → Q waves → T inversions)
• Full coronary territory localization table (anterior, inferior, lateral, posterior, RV)
• Wellens syndrome, De Winter pattern
• Pseudo-infarction patterns

• Congenital LQTS (LQT1/2/3 - genes, T-wave morphology, triggers, treatment)
• Acquired QT prolongation drugs
• Torsades management: MgSO4, pacing, drug avoidance

• Hyperkalemia progressive sequence + treatment
• Hypokalemia, hypocalcemia, hypercalcemia, hypothermia (Osborn J waves)

• 1st degree, Mobitz I (Wenckebach), Mobitz II, 2:1 block, 3rd degree (complete)
• AV dissociation vs complete heart block distinction

• Short PR + delta wave + wide QRS triad
• Danger of AF with WPW; never give AV nodal blockers; procainamide or cardioversion

• ST elevation: STEMI vs pericarditis vs early repolarization vs Brugada vs LV aneurysm vs Takotsubo
• ST depression: ischemia, digoxin, LVH strain, RBBB
• T-wave inversion: Wellens, RVH, PE (S1Q3T3), CVA T-waves, HCM, cardiac memory

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