Atrial cardiomyocytes lose contractile reserve with increased frequency and adrenergic stimulation in a murine HFpEF model
H Zhang, J Song, H Lin, A Johnston, S Nicklin, E Cameron, E MacDonald, C LoughreyAbstract
Background
Heart failure with preserved ejection fraction (HFpEF) is characterised by impaired cardiac reserve during periods of elevated heart rate. Left atrial (LA) dysfunction is a key determinant of symptoms and outcomes in HFpEF, but how individual cardiomyocytes (CMs) contribute to this remains unclear.
Purpose
To determine how atrial CMs respond to increased heart rate and β-adrenergic stimulation in a HFpEF mouse to link cellular changes with in vivo LA impairment.
Methods
Male C57BL/6N mice (9 weeks old) underwent a two-hit model (2HM) HFpEF protocol (high-fat diet + L-NAME, 14 weeks; n=4) or served as controls (CTRL, n=5). In the same animals, LA reservoir strain (LASr%) was quantified by speckle-tracing echocardiography prior to tissue collection. Isolated atrial cardiomyocytes (CMs, 3-5 CMs per animal, 36 cells in total) were field-stimulated at 1,2, and 3 Hz for 30 seconds at each frequency. Finally, cells were returned to 1 Hz to stabilize before superfusion with 10 nM isoproterenol (ISO). Contractility was assessed by cell edge length detection.
Results
2HM atrial CMs showed markedly reduced fractional shortening (FS) at all pacing frequencies vs CTRL (~4% vs ~9%; group effect p<0.0001). Peak departure and return velocities were blunted in 2HM, with impaired augmentation at higher pacing frequencies. Mechanical relaxation was prolonged in 2HM (τ: 67 vs 43 ms; p=0.042). β-adrenergic inotropic reserve was severely impaired (10 nM ISO Peak FS%: 4.96% vs 8.94%; p=0.0004), with blunted peak departure and return velocities (p<0.05). Atrial CM fractional shortening correlated strongly with in vivo LASr% across all frequencies (r=0.88–0.90; p<0.002).
Conclusions
Atrial CMs in a murine HFpEF model exhibit contractile dysfunction, with impaired rate-dependent adaptation and severely impaired β-adrenergic reserve. The strong correlation between cellular fractional shortening and in vivo LASr% provides a translational cellular mechanism for LA dysfunction in HFpEF, with direct relevance to the loss of atrial contractile reserve that is observed clinically.Figure 1.Experimental Design OverviewFigure 2.CM Contractility_LA Strain in HFpEF