C-type natriuretic peptide attenuates diastolic dysfunction and cardiac fibrosis in a rat model of heart failure with preserved ejection fraction
T Soeki, E Uematsu, K Tezuka, T K Takahashi, T Matsuura, T N Takahashi, Y Kawabata, M Kadota, T Hara, T Ise, K Yamaguchi, S Yagi, H Yamada, K Kangawa, M SataAbstract
Background
C-type natriuretic peptide (CNP) regulates cardiac hypertrophy and fibrosis without affecting blood pressure; however, its effect on heart failure with preserved ejection fraction (HFpEF) remains unclear.
Purpose
This study explored whether CNP administration improves left ventricular (LV) diastolic distensibility and hemodynamic parameters in rats with HFpEF through its antifibrotic and antihypertrophic actions.
Methods
Dahl salt-sensitive rats on a diet containing 8% NaCl were used as a hypertensive HFpEF model. The rats received treatment with CNP at 0.1 μg/kg/min (n = 9) or vehicle (n = 10) for 4 weeks. The control rats (n = 7) were fed a low-salt diet containing 0.3% NaCl for 8 weeks.
Results
In the hemodynamic study, CNP administration significantly ameliorated LV diastolic dysfunction, as indicated by the increased -dP/dt min and reduced LV end-diastolic pressure in the HFpEF model (-dP/dt min: HFpEF+placebo, 4913±298 mmHg/s; HFpEF+CNP, 6030±250 mmHg/s; p < 0.05; LV end-diastolic pressure: HFpEF+placebo, 14.0±1.4 mmHg; HFpEF+CNP, 9.7±0.8 mmHg/s; p < 0.05). However, it did not affect arterial pressure. Furthermore, CNP effectively diminished the increase in morphometric collagen volume fraction within the left ventricle (Figure). These CNP effects were attributed to the inhibition of the upregulation of connective tissue growth factor mRNA levels. CNP also attenuated the increased heart weight-to-body weight ratio but did not reduce echocardiographic LV wall thickness in HFpEF rats.
Conclusion
CNP administration improved diastolic function, possibly through its antifibrotic effect. These data suggest the potential applicability of CNP in the treatment of HFpEF.Figure