Abnormal calcium homeostasis in heart failure with preserved ejection fraction is related to both reduced contractile...

Area of Science:

• Cardiology
• Biophysics
• Computational Biology

Background:

• Heart failure with preserved ejection fraction (HFpEF) comprises 50% of heart failure cases.
• HFpEF is characterized by impaired left ventricular relaxation and increased stiffness.
• Known associations include abnormal calcium handling, ion channel remodeling, and concentric left ventricle hypertrophy (LVH).

Purpose of the Study:

• To investigate the electro-mechanical effects of HFpEF-induced cellular changes.
• To develop multiscale computational models of the human left ventricle incorporating HFpEF characteristics.
• To understand the cellular mechanisms underlying impaired cardiac electromechanical function in HFpEF.

Main Methods:

• Developed multiscale computational models of the human left ventricle (single cell to 3D organ).
• Incorporated HFpEF-specific alterations in calcium handling, ion channel function, and LVH.
• Simulated ventricular cell and organ-level electro-mechanical dynamics under varying conditions.

Main Results:

• At the cellular level, HFpEF reduced systolic calcium, decreasing contractile force, and elevated diastolic calcium, causing abnormal residual diastolic force.
• These cellular electro-mechanical abnormalities were exacerbated by increased heart rate.
• At the 3D organ level, concentric LVH maintained left ventricular ejection fraction, despite cellular dysfunction.

Conclusions:

• Computational models successfully replicated observed HFpEF clinical features.
• Findings provide insights into the cellular basis of impaired electromechanical function in HFpEF.
• The study highlights the complex interplay between cellular changes and organ-level function in HFpEF.