Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure

Area of Science:

• Cardiovascular physiology
• Cardiac electrophysiology
• Molecular cardiology

Background:

• End-stage heart failure (HF) is linked to altered cardiac conduction velocity (CV), increasing arrhythmia risk.
• Understanding the temporal relationship between CV changes, connexin 43 (Cx43) properties, and mechanical function during HF development is crucial.

Purpose of the Study:

• To investigate the time course of CV changes in relation to Cx43 alterations and mechanical function during the progression of heart failure.
• To elucidate the sequence of events in cardiac remodeling, focusing on Cx43 expression, distribution, phosphorylation, and their impact on CV and mechanical function.

Main Methods:

• High-resolution optical mapping was employed in arterially perfused canine myocardial preparations.
• Dogs were subjected to rapid pacing for varying durations (0-21 days) to induce progressive heart failure remodeling.
• Conduction velocity (CV) was measured and compared with left ventricular end-diastolic pressure (LVEDP) and dynamic changes in Cx43 properties.

Main Results:

• Conduction velocity (CV) was preserved in early remodeling stages (3-7 days) but significantly reduced in later stages (associated with increased LVEDP).
• Early, sustained downregulation of pan-Cx43 preceded mechanical dysfunction and CV slowing.
• Changes in Cx43 phosphorylation correlated more closely with HF onset, while Cx43 lateralization occurred late, coinciding with marked CV reduction.

Conclusions:

• Conduction slowing in heart failure is a late phenomenon, occurring after significant remodeling.
• Connexin 43 (Cx43) downregulation is an early event in HF development, preceding functional decline.
• Altered Cx43 phosphorylation and lateralization are key events associated with the progression of heart failure and conduction abnormalities.