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Published on: July 14, 2021
Na+/H+ exchange inhibition attenuates left ventricular remodeling and preserves systolic function in
Giuseppe Marano1, Alessandro Vergari, Liviana Catalano
1Laboratorio di Farmacologia, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy. gmarano@iss.it
Insights
Inhibiting the Na+/H+ exchanger isoform 1 (NHE-1) with cariporide prevented cardiac hypertrophy and preserved left ventricular function in mice subjected to pressure overload. This suggests NHE-1 is a key target for treating heart failure.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Cardiac Remodeling
Background:
- Cardiac hypertrophy is a response to increased afterload.
- Na+/H+ exchanger (NHE) inhibition shows promise in animal models for reducing cardiac hypertrophy and mitigating myocardial infarction.
- The role of NHE isoform 1 (NHE-1) in left ventricular (LV) function under chronic pressure overload requires further investigation.
Purpose of the Study:
- To investigate the chronic effects of cariporide, a selective NHE-1 inhibitor, on left ventricular systolic and diastolic function.
- To assess the impact of NHE-1 inhibition on cardiac hypertrophy and remodeling induced by pressure overload.
Main Methods:
- Male CD-1 mice underwent thoracic aortic banding to induce cardiac pressure overload.
- Mice received either a control diet or a diet supplemented with cariporide (6000 p.p.m.).
- Echocardiography and cardiac catheterization were used to assess LV dimensions, systolic, and diastolic function at 2 and 5 weeks post-surgery. Histological analysis was also performed.
Main Results:
- Cariporide treatment significantly attenuated left ventricular hypertrophy (LVH) and preserved systolic function and contractility in banded mice compared to vehicle-treated controls at both 2 and 5 weeks.
- While diastolic function was not significantly different, cariporide prevented the LV chamber enlargement and systolic dysfunction observed in vehicle-treated banded mice at 5 weeks.
- Histological analysis revealed that cariporide reduced cardiomyocyte hypertrophy but did not affect myocardial fibrosis in banded mice.
Conclusions:
- The hypertrophic response to pressure overload is dependent on Na+/H+ exchanger isoform 1 (NHE-1) activity.
- Chronic inhibition of NHE-1 with cariporide effectively prevents the deterioration of left ventricular performance during pressure overload.
- NHE-1 inhibition represents a potential therapeutic strategy for managing cardiac hypertrophy and preventing heart failure progression.
Abstract:
Cardiac hypertrophy is a homeostatic response to elevated afterload. Na+/H+ exchanger (NHE) inhibition reduces the hypertrophic response in animal models of left ventricular hypertrophy (LVH) and myocardial infarction. We examined the effect of chronic treatment with cariporide, a selective inhibitor of Na+/H+ exchanger isoform 1 (NHE-1), on left ventricular (LV) systolic and diastolic function under pressure overload conditions. Male CD-1 mice were randomized to receive either a control diet or an identical diet supplemented with 6000 p.p.m. of cariporide. Cardiac pressure overload was induced by thoracic aortic banding. LV dimension and systolic and diastolic function were assessed in sham and banded mice by echocardiography and cardiac catheterization 2 and 5 weeks after surgery. Histological analysis was also performed. After 2 weeks of pressure overload, the vehicle-treated banded mice (Veh-Bd) had enhanced normalized LV weight (about +50%) and normal chamber size and function, whereas cariporide-treated banded mice (Car-Bd) showed a preserved contractility and systolic function despite a marked attenuation of LVH. Diastolic function did not differ significantly among groups. After 5 weeks, the Veh-Bd developed LV chamber enlargement and systolic dysfunction as evidenced by a 16% increase in LV end-diastolic diameter, a 36% decrease in myocardial contractility, and a 26% reduction in percent fractional shortening. In contrast, Car-Bd showed an attenuated increase in LV mass, normal chamber size, and a maintained systolic function. A distinct histological feature was that in banded mice, cariporide attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. In conclusion, the results of the present study indicate that (i) the hypertrophic response to pressure overload is dependent on NHE-1 activity, and (ii) at the 5-week stage, banding-induced deterioration of LV performance is prevented by NHE-1 inhibition.British Journal of Pharmacology (2004) 141, 526-532. doi:10.1038/sj.bjp.0705631
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