Primary Heart Muscle Disease

Primary Heart Muscle Disease：contains thick myosin and thin actin filaments，their relative motion will leads to muscle contraction/relaxation。

Primary Heart Muscle Disease

• Symptom
  • heart is abnormally enlarged, thickened and/or stiffened, reducing its ability to pump.
  • It typically results in 2 types of abnormal hearts
    • dialeted
      • due to compensatory remodeling
        • weakened contractile function
        • accelerate functional deterioration
        • onset of heart failure
    • hypertrophic
      • due to fibrosis
        • normal contractile function
        • leads to acrdiac stiffnes
        • impaired ventricular relaxation
          • shortness of breath and chest pain
          • at risk of heart failure and sudden death
      • 1 in 500 individual
    • results
      • increase myocardial strain
      • increase metabolic demands
      • impede ventricular relaxation
      • compromise coronary artery blood flow
• mechanism
  • show genetic heterogeneity
    • about 10 genes
  • Mutations identified on contractile apparatus (within sacromere)
    • Heart muscle contraction mechanism
      • Muscle contraction mechanism
        • sacromere
          • functional unit of contraction in myosin
          • contains thick myosin and thin actin filaments
            • their relative motion will leads to muscle contraction/relaxation
        • tropanin
          • a Ca2+ binding protein complex normally associates within actin
        • Ca2+ induced muscle contraction initiation
          • Ca2+ first binds to tropoin complex. troponin complex will relives troponin I, troponin I inhibits the actin-myosin interactions, actin and myosin get tightly interaction after the troponin I dissociates.
        • ATP induced muscle contraction restortion
          • ATP first binds to myosin, the myosin undergoes a resulting confotmational change in its actin binding site, and the ATP is immediately hydrolysiszed, the conformation of myosin restored. After this process, the myosin will detached from actin. The muscle will become relaxed again.
    • cardiac myosin heavy chain
      • Arg403Gln
        • enhance actin-activated myosin ATPase activity
        • this will increase force generation and accelerated actin filaments sliding
          • gain of myosin function, enhanced cardiac performance
        • this also increases energy consumption
          • die of myocytes, the cardiac fibroblasts would replace it and leads to "replacement fibrosis"
    • cardiac troponin T
    • α-tropomyosin
    • cardiac myosin binding protein C
    • cardiac actin
    • essential and regulatory myosin light chain
    • Common results
      • uncouple mechanical coordination within myosin heads
      • increase energy consumption
  • Mutations identified on force transmission apparatus(from sacromere to cytoskeleton and the extracellular matrix)
    • Force propagation mechanism
    • from sacromere to cytoskeleton
    • from cytoskeleton to extracellular matrix
      • by an oligomeric complex containing dystrophin and sarcoglycans beneath the myocyte plasma membrane.
        • DuChenn muscular dystrophies are caused by the mutation on dystrophin
        • a virus encoding protease: Enteroviral protease 2A can causes the same symptom with DMD
      • failure in this functional complex can cause heart muscle disease
    • The failure at this section may causes the cardiac compensitory remodeling