## Cardiac Action Potential in Acute Myocardial Ischaemia ### The Ischaemic Cascade and ATP Depletion **Key Point:** Acute myocardial ischaemia rapidly depletes ATP, causing failure of the Na⁺/K⁺-ATPase. This pump normally extrudes 3 Na⁺ and imports 2 K⁺, maintaining the resting membrane potential (Phase 4) at approximately −85 mV. When the pump fails, **Phase 4 is the primary phase disrupted** — the resting membrane potential becomes less negative (depolarized), which is the root cause of all downstream electrophysiological disturbances. ### Why Phase 4 Is Most Critically Affected 1. **ATP Depletion → Na⁺/K⁺-ATPase Failure:** - The Na⁺/K⁺-ATPase consumes ~25–30% of total cardiac ATP. - Within 1–2 minutes of ischaemia, ATP drops precipitously. - The pump stops → **Na⁺ accumulates intracellularly**, **K⁺ accumulates extracellularly**. 2. **Consequences for Phase 4 (Resting Membrane Potential):** - The resting membrane potential is maintained primarily by the K⁺ equilibrium potential (Ek) and the electrogenic Na⁺/K⁺-ATPase. - With pump failure and rising extracellular K⁺, the K⁺ gradient collapses → Ek becomes less negative. - The resting membrane potential shifts from ~−85 mV toward ~−60 mV or less negative. - This **loss of negative resting potential** (Phase 4 depolarization) is the hallmark of ischaemic injury. - It is directly responsible for the **injury current** that produces ST elevation on ECG. 3. **Downstream Consequences of Phase 4 Depolarization:** - Partial depolarization inactivates fast Na⁺ channels (Phase 0 impaired) → slowed conduction. - Reduced driving force for K⁺ efflux impairs Phase 3 repolarization → QT prolongation. - Intracellular Na⁺ accumulation reverses the Na⁺/Ca²⁺ exchanger → Ca²⁺ overload → arrhythmias and cell death. ### Why the Other Options Are Incorrect | Option | Why Incorrect | |--------|--------------| | **B) Phase 3: failure of K⁺ efflux** | Phase 3 is secondarily impaired, but the *primary* and *initiating* defect is Phase 4 depolarization from Na⁺ accumulation. Phase 3 failure is a downstream consequence. | | **C) Phase 2: prolongation due to unopposed Ca²⁺** | In ischaemia, Phase 2 is typically *shortened* (not prolonged) because cytoplasmic Ca²⁺ overload and mitochondrial sequestration reduce net inward Ca²⁺ current. Prolonged Phase 2 is seen in hypercalcaemia or with certain drugs. | | **D) Phase 0: failure of fast Na⁺ channels** | Phase 0 failure is a *consequence* of Phase 4 depolarization (inactivation of Na⁺ channels at less negative potentials), not the primary mechanism. The option also imprecisely states "depolarization preventing opening" rather than "inactivation." | ### ECG Correlation | ECG Finding | Mechanism | Phase Affected | |-------------|-----------|----------------| | **ST elevation** | Injury current: ischaemic cells at −60 mV vs. normal cells at −85 mV | **Phase 4** (primary) | | Prolonged QT | Delayed repolarization | Phase 3 (secondary) | | Loss of R wave | Conduction block | Phase 0 (secondary) | | Peaked T waves (early) | Rapid repolarization in border zone | Phase 3 | **Clinical Pearl:** The **"injury current"** producing ST elevation in inferior STEMI (leads II, III, aVF) directly reflects Phase 4 depolarization in the ischaemic zone. The voltage difference between the partially depolarized ischaemic cells (~−60 mV) and normal cells (~−85 mV) creates a current of injury visible on surface ECG. This is the most direct electrophysiological consequence of Na⁺/K⁺-ATPase failure and intracellular Na⁺ accumulation. **High-Yield:** In acute MI, the three zones are: 1. **Central necrotic zone:** Dead cells, no action potentials. 2. **Ischaemic (injury) zone:** ATP depleted, Na⁺/K⁺-ATPase failed → **Phase 4 depolarized** → ST elevation. 3. **Border zone:** Metabolically stressed, repolarization abnormal → T-wave inversion. **Mnemonic: "PHASE 4 FIRST"** — In ischaemia, the resting potential is lost first (Phase 4), which then cascades to impair Phase 0 (conduction), Phase 3 (repolarization), and ultimately causes Ca²⁺ overload and cell death. [cite: Guyton & Hall Textbook of Medical Physiology 14e, Ch 10; Harrison's Principles of Internal Medicine 21e, Ch 297; Ganong's Review of Medical Physiology 26e, Ch 5]
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