The Brugada syndrome pattern on ECG (coved-type ST elevation in V1–V2) results from dysfunction of which molecular channel, and what is the consequence for action potential phase 1?

• A Gain-of-function KCNQ1; increased IKs shortens action potential duration in right ventricular epicardium
• B Loss-of-function KCNH2 (hERG); impaired IKr prolongs QTc and creates early afterdepolarizations
• C Loss-of-function CACNA1C (Cav1.2); reduced ICaL causes phase 2 re-entry in right ventricle
• D Loss-of-function SCN5A (Nav1.5); reduced fast Na⁺ current unmasks Ito-driven phase 1 notch in epicardium ✓

Explanation

Brugada syndrome is most commonly caused by loss-of-function mutations in SCN5A encoding Nav1.5 (fast cardiac sodium channel). The reduced INa phase 0 current unmasks the prominent transient outward K⁺ current (Ito) in right ventricular epicardium, which endocardium lacks. This Ito-dominant phase 1 creates a pronounced notch and shortens epicardial action potential relative to endocardium — generating a transmural voltage gradient that appears as ST elevation in V1–V2. Phase 2 re-entry from this dispersion of repolarization can trigger ventricular fibrillation.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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