3.2 Systemic Clinical Physiology & Homeostasis

Systemic clinical physiology in MRCP(UK) Part 1 tests haemodynamic principles, respiratory gas calculations, and neurohumoral fluid balance.

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1. Cardiovascular Mechanics & Reflexes

The Cardiac Cycle & Pressure-Volume Loops

The left ventricular cycle features six phases:

1. Isovolumetric Contraction: QRS depolarisation triggers contraction; LV pressure exceeds left atrial pressure, closing the mitral valve (S1). All valves remain closed while intraventricular pressure spikes.
2. Rapid Ejection: LV pressure exceeds aortic diastolic pressure (~80 mmHg); aortic valve opens, rapidly discharging stroke volume.
3. Reduced Ejection: Ventricular repolarisation begins (T wave); outflow velocity slows.
4. Isovolumetric Relaxation: LV pressure falls below aortic pressure, closing the aortic valve (S2; physiological splitting widens on inspiration due to delayed P2 from augmented venous return).
5. Rapid Filling: LV pressure drops below left atrial pressure, opening the mitral valve. Rapid filling generates an S3 in volume overload or dilated cardiomyopathy.
6. Diastasis & Atrial Systole: Atrial contraction adds 15–20% of EDV ("atrial kick"). Contracting into a stiff ventricle generates a pathological S4.

The PV loop defines stroke volume (SV = EDV - ESV) and ejection fraction (EF = SV / EDV):

• Increased Preload: Shifts EDV rightward along the diastolic curve, increasing SV via Frank-Starling mechanics.
• Increased Afterload: Raises peak systolic pressure, increases ESV, and decreases SV.
• Increased Inotropy: Shifts the end-systolic curve (ESPVR) leftward, increasing SV and reducing ESV.

Systemic Vascular Resistance & Coronary Perfusion

SVR = [(MAP - CVP) / CO] × 80. By Poiseuille's law (R ∝ 1/r⁴), arteriolar radius is the chief vascular resistance regulator.

The left ventricular subendocardium is perfused almost exclusively in diastole:

$\text{CPP} = \text{Aortic Diastolic Pressure} - \text{LVEDP}$

Tachycardia shortens diastole disproportionately. Aortic regurgitation reduces aortic diastolic pressure, while aortic stenosis elevates LVEDP; both severely reduce CPP, precipitating subendocardial ischaemia.

Autonomic Reflex Arcs

• Baroreceptors: Carotid sinus (CN IX) and aortic arch (CN X) mechanoreceptors project to the medullary nucleus tractus solitarius (NTS). Elevated pressure increases firing, stimulating vagal parasympathetic nuclei (bradycardia) and inhibiting sympathetic outflow (vasodilatation).
• Chemoreceptors: Peripheral bodies (carotid CN IX, aortic CN X) detect hypoxaemia (PaO₂ < 8.0 kPa), hypercapnia, and acidosis. Central chemoreceptors in the ventrolateral medulla sense [H⁺] in CSF generated by diffusing arterial CO₂.

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2. Respiratory Gas Exchange & Mechanics

Lung Volumes, Capacities & Dead Space

• Volumes: Tidal Volume (TV ~500 mL), Inspiratory Reserve Volume (IRV ~3,000 mL), Expiratory Reserve Volume (ERV ~1,100 mL), Residual Volume (RV ~1,200 mL). RV cannot be measured by spirometry; it requires helium dilution or plethysmography.
• Functional Residual Capacity (FRC = ERV + RV): Resting volume where inward lung recoil balances outward chest wall recoil.
• Physiological Dead Space (VD): Calculated via the Bohr-Enghoff equation: $\text{VD} / \text{VT} = (\text{PaCO}_2 - \text{PECO}_2) / \text{PaCO}_2$ Normal ratio is 0.20–0.35; it increases in pulmonary embolism and emphysema.

Alveolar Gas Equation & A-a Gradient

Expected alveolar oxygen tension: $\text{PAO}_2 = \text{FiO}_2 \times (\text{Patm} - \text{PH}_2\text{O}) - (\text{PaCO}_2 / \text{R})$ On room air at sea level: PAO₂ ≈ 20.0 kPa - (PaCO₂ / 0.8).

• A-a Gradient (PAO₂ - PaO₂): Normal is < 2.0 kPa (or Age/4 + 4 mmHg).
• Normal A-a with Hypoxaemia: Indicates alveolar hypoventilation (sedatives, neuromuscular disease) or high altitude.
• Elevated A-a with Hypoxaemia: Indicates V/Q mismatch, shunt, or diffusion barrier defect.

V/Q Mismatch vs. True Shunt

• V/Q Mismatch (COPD, asthma): Low V/Q units readily respond to modest supplemental oxygen.
• True Shunt (V/Q = 0; ARDS, consolidation, right-to-left shunts): Blood bypasses ventilated alveoli. Hallmark: Hypoxaemia fails to correct with 100% supplemental oxygen.

Oxygen-Haemoglobin Dissociation Curve

Normal P50 is 3.5 kPa (26.6 mmHg).

• Right Shift (decreased affinity, O2 release): Acidosis (Bohr effect), hypercapnia, hyperthermia, elevated 2,3-DPG.
• Left Shift (increased affinity, O2 holding): Alkalosis, hypocapnia, hypothermia, low 2,3-DPG, HbF, carboxyhaemoglobin.

MRCP Exam Pearl: Oxygen-Induced Hypercapnia in COPD: High-flow oxygen worsens acidosis primarily by reversing hypoxic pulmonary vasoconstriction (redirecting blood to unventilated alveoli, increasing dead space) and via the Haldane effect (oxygenating Hb displaces CO₂ into plasma). Target SpO₂ is 88–92%.

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3. Renal Microcirculation & Neurohumoral Regulation

Glomerular Filtration Dynamics

$\text{GFR} = K_f \times [(P_{GC} - P_{BS}) - (\pi_{GC} - \pi_{BS})]$ Autoregulation (MAP 80–180 mmHg) relies on myogenic responses and tubuloglomerular feedback (macula densa detects luminal NaCl, releasing adenosine to constrict afferent arterioles).

• Prostaglandins: Dilate afferent arterioles. NSAIDs block this, causing afferent constriction and acute GFR drops.
• Angiotensin II: Constricts efferent arterioles to preserve P_GC. ACE inhibitors dilate efferent arterioles, reducing GFR during hypoperfusion.

Countercurrent Multiplication & Urea Recycling

The loop of Henle establishes a hypertonic medullary gradient (300 to 1,200 mOsm/kg):

• Thin Descending Limb: Permeable to water via aquaporin-1 (AQP1); impermeable to solutes.
• Thick Ascending Limb (TAL): Impermeable to water; actively transports Na⁺, K⁺, and 2Cl⁻ via apical NKCC2 cotransporters (inhibited by furosemide), creating a 200 mOsm/kg single effect.
• Urea Recycling: ADH stimulates UT-A1/A3 transporters in medullary collecting ducts, recycling urea to generate ~50% of papillary hypertonicity. Vasa recta hairpin loops act as countercurrent exchangers to prevent solute washout.

Endocrine Fluid Homeostasis

• RAAS: Juxtaglomerular renin cleaves angiotensinogen → Ang I → Ang II (via ACE). Ang II stimulates adrenal aldosterone, which binds mineralocorticoid receptors in principal cells to upregulate apical ENaC channels and basolateral Na⁺/K⁺-ATPase (sodium/water retention, potassium/hydrogen excretion).
• Vasopressin (ADH): Released from posterior pituitary upon hyperosmolality (> 280 mOsm/kg) or hypovolaemia. Binds basolateral V2 receptors (Gs-coupled), activating cAMP/PKA to insert Aquaporin-2 (AQP2) water channels into apical membranes.
• ANP: Released by stretched atria. Activates guanylyl cyclase (↑ cGMP), dilating afferent and constricting efferent arterioles to raise GFR, while inhibiting renin, aldosterone, and tubular sodium reabsorption.