A 55-year-old hypertensive woman undergoes autopsy following sudden cardiac death. The left ventricle shows concentric hypertrophy, and histology reveals myocyte disarray, interstitial fibrosis, and thickened intramural coronary arterioles. No obstructive epicardial coronary artery disease is found. Which molecular pathway is most central to the pathogenesis of pressure overload-induced cardiac hypertrophy?
- A Calcineurin (phosphatase)-NFAT signaling pathway (pathological hypertrophy in pressure overload) ✓
- B PI3K-Akt-mTOR pathway (physiological hypertrophy in athletes)
- C MAPK-ERK1/2 pathway exclusively (growth factor receptor activation)
- D cGMP-PKG pathway (anti-hypertrophic, downstream of NO and BNP)
Explanation
Pressure overload (hypertension, aortic stenosis) triggers intracellular calcium signaling, activating the phosphatase calcineurin (protein phosphatase 2B). Calcineurin dephosphorylates NFAT (nuclear factor of activated T cells) transcription factors, which translocate to the nucleus and activate fetal gene program — re-expression of beta-myosin heavy chain, atrial natriuretic factor, and skeletal alpha-actin. This calcineurin-NFAT axis drives pathological concentric hypertrophy with fibrosis and increased risk of sudden death. PI3K-Akt-mTOR drives physiological hypertrophy (exercise, pregnancy) without fibrosis. cGMP-PKG is anti-hypertrophic.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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