HCM

Question 1

Compensatory model of HCM pathogenesis

Answer 1

Incorporation of mutant sarcomeric proteins depresses contractile function, and subsequent neuroendocrine and mechanical responses leads to compensatory hypertrophy

Question 2

Limitations of the compensatory model of HCM pathogenesis

Answer 2

Model fails to explain 3 cardinal features of HCM:
1. Decreased contractility cannot be sole stimulus for hypertrophy: MYH7 mutants show enhanced motor activity, Trop T shows reduced force but increased actin translocation, thin filament proteins (Trop I, tropomyosin) show increased Ca sensitivity of force production.
2. Hypertrophy in HCM is asymmetric and more gross than concentric hypertrophy seen in hypertension
3. Hypertrophy usually only apparent from puberty and progresses little. Compensation should start since birth?

Question 3

Outline the Energy Depletion Hypothesis of HCM pathogenesis

Answer 3

• Sarcomeric mutations = structural and functional abnormalities –> inefficient ATP utilisation
• Inefficient ATP use –> increased energy demands (more ATP required to achieve same level of contraction)
• Hypercontractility and increased workload also increase energy demands
• Element of impaired energy supply from mitochondrial dysfunction or microvascular dysfunction (limited O2 and nutrient supply)
• Combination of above –> energy deficit –> stress –> hypertrophic signalling pathways (to compensate increased increased workload - AMPK pathway/ mTOR)
• Hypertrophy copes with increased workload –> remodelling over time