Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic...

Area of Science:

• Cardiovascular Physiology
• Diabetology
• Pharmacology

Background:

• Diabetes mellitus is frequently associated with heart failure with preserved ejection fraction (HFPEF).
• Currently, no established therapies effectively improve cardiovascular outcomes in HFPEF patients.
• Understanding myocardial function and ventricular-arterial coupling in diabetes-related HFPEF is crucial.

Purpose of the Study:

• To characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes.
• To investigate the therapeutic effect of selective heart rate (HR) reduction via If-inhibition in this HFPEF model.

Main Methods:

• Comparison of control mice, diabetic mice (db/db), and db/db mice treated with the If-inhibitor ivabradine (db/db-Iva).
• Assessment of aortic distensibility using magnetic resonance imaging.
• Left ventricular (LV) pressure-volume analysis in isolated working hearts, alongside biochemical and histological analyses.

Main Results:

• Diabetic db/db mice exhibited increased aortic stiffness and fibrosis, which were mitigated by ivabradine treatment.
• LV end-systolic elastance (Ees) was elevated in db/db mice, indicating impaired contractility; HR reduction normalized Ees and improved other contractility markers.
• Diabetic mice showed prolonged active relaxation and reduced end-diastolic capacitance, both ameliorated by HR reduction.

Conclusions:

• Selective HR reduction through If-inhibition improved vascular stiffness, LV contractility, and diastolic function in a diabetic HFPEF mouse model.
• If-inhibition presents a promising therapeutic strategy for HFPEF.
• Further investigation in human clinical trials is warranted to confirm these findings.