The Frank-Starling mechanism is demonstrated experimentally in an isolated heart preparation. At constant contractility and afterload, increasing end-diastolic volume from 120 mL to 150 mL increases stroke volume from 70 to 90 mL. The underlying molecular mechanism at the sarcomere level is BEST explained by:

• A Increased stretch increases the sensitivity of troponin C to calcium (Ca²⁺) by optimizing the spatial relationship between myosin heads and actin, and may increase myofilament calcium sensitivity via titin-mediated signaling ✓
• B Increased stretch directly opens stretch-activated L-type Ca²⁺ channels in the sarcolemma, increasing intracellular Ca²⁺ and contractile force
• C Increased EDV increases wall stress, triggering hypertrophy gene expression that acutely increases myosin heavy chain isoform switching to the faster V1 form
• D Increased stretch lengthens sarcomeres to optimal overlap (2.2 μm) where maximum number of cross-bridges form; beyond this length, overlap decreases and force falls

Explanation

The Frank-Starling mechanism operates through increased myofilament calcium sensitivity at longer sarcomere lengths. At the molecular level, stretch increases the affinity of troponin C for calcium — the same intracellular calcium concentration produces a greater contractile response. Additionally, titin (the giant elastic protein connecting myosin to the Z-disk) undergoes conformational changes under stretch that may enhance myosin-actin interaction and signal to increase Ca²⁺ sensitivity. While sarcomere length optimization (option D) was the historic explanation (Starling's original model), it has been modified: cardiac sarcomeres in intact hearts rarely operate on the descending limb of the length-tension curve; the primary mechanism is increased Ca²⁺ sensitivity. Option B (stretch-activated Ca²⁺ channels) contributes to mechano-calcium coupling but is not the primary Frank-Starling mechanism. Option C describes long-term adaptation.

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

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