Molecular and structural transition mechanisms in long-term volume overload

Area of Science:

• Cardiology
• Molecular Biology
• Physiology

Background:

• Early-phase experimental volume overload (VO) shows adaptive phenotypes.
• Wall stress-matched pressure overload (PO) is maladaptive.
• The transition from adaptation to heart failure (HF) in long-term VO requires investigation.

Purpose of the Study:

• To investigate the transition from adaptation to heart failure (HF) in long-term experimental volume overload (VO).

Main Methods:

• FVB/N wild-type mice underwent VO via aortocaval shunt.
• Serial echocardiography monitored left ventricular ejection fraction.
• Heart failure development was assessed by organ weight, mortality, and molecular markers.

Main Results:

• Long-term VO induced HF, evidenced by increased mortality and organ weight.
• Maladaptive remodeling included reduced titin phosphorylation (increased stiffness) and no increased fibrosis.
• Molecular changes involved fetal gene re-expression, activated CaMKII, decreased Akt phosphorylation, oxidative stress, and apoptosis.

Conclusions:

• Transition to HF in VO involves decreased Akt and increased CaMKII signaling, oxidative stress, and apoptosis.
• Increased sarcomeric stiffness, due to titin hypophosphorylation, characterizes VO-induced HF.
• Myocyte loss and dysfunction from increased stiffness may drive HF progression.