Heart Failure & Hypertrophy

Question 1

Myosin structure/isoforms present in myocytes

Answer 1

• Alpha and Beta myosin heavy chain isoforms are found in the heart
• aa, aB, and BB heterodimers have distinct ATPase activity and functional properties
• the ratio of these isoforms varies across species and throughout development

Question 2

Myosin isoforms in pathological vs. physiological cardiac hypertrophy

Answer 2

• Myosin isoform and ATPase shifts are seen in two phenotypically distinct models of cardiac hypertrophy
• Pathological hypertrophy (chronic hypertension, aortic valve stenosis)
  
  • ​Increase in BB MHC
  • Decrease in ATPase activity
• ​Physiological hypertrophy (exercise, pregnancy)
  
  • ​Increase in aa MHC
  • Increase in ATPase

Question 3

Increased cytosolic calcium contribution to development of CHF

Answer 3

• increased cytosolic calcium –> impaired myocyte relaxation
• Increased L-type Ca2+ current
• Reduced SERCA pump function – via transcriptional down-regulation of SERCA and post-translational modification of PLB which increases its inhibition
  
  • ​Calcineurin (Ca2+ dependent phosphatase) targets NFAT; dephosphorylated NFAT moves from the cytosol to the nucleus where it acts as a transcription factor for genes related to cardiac remodeling (possibly B MHC)
  • Calcineurin is activated slowly – requires weeks/months+ of chronic activation
  • SERCA2 gene transfer corrects mechanical defects in cardiocytes from animals with heart failure

Question 4

Alterations in sympathetic signaling and contribution to development of CHF

Answer 4

• Early/acute
  
  • ​PKA activation –> increased inotropy
  • This is adaptive in the acute setting
• ​Late/chronic
  
  • ​​PKCe, PKD, CamK become activated in response to chronic sympathetic stimuli

Question 5

LV fxn following an acute insult

Answer 5

sharp acute decline followed by increasing deterioration in function that continue to occur chronically