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A Rat Model of Pressure Overload Induced Moderate Remodeling and Systolic Dysfunction as Opposed to Overt Systolic Heart Failure
Published on: April 30, 2020
Reverse electromechanical modelling of diastolic dysfunction in spontaneous hypertensive rat after
Yen-Ling Sung1,2, Ting-Tse Lin1,3,4, Jhen-Yang Syu1
1Institute of Biomedical Engineering, College of Electrical and Computer Engineering, National Chiao Tung University, Hsinchu, 300, Taiwan.
Insights
Sacubitril/valsartan (SV) treatment in hypertensive rats reduced ventricular arrhythmias and improved cardiac function by modulating KCNN2 channel expression. This study demonstrates SV’s potential in managing hypertensive heart disease and preventing sudden cardiac death.
Area of Science:
- Cardiovascular Research
- Hypertensive Heart Disease
- Cardiac Electrophysiology
Background:
- Hypertension is a major risk factor for left ventricular hypertrophy, diastolic dysfunction, heart failure, and sudden cardiac death.
- Sacubitril/valsartan (SV) is known to reduce sudden cardiac death in heart failure with systolic dysfunction, but its effect on diastolic dysfunction is unclear.
- This study investigates the anti-arrhythmic effects of SV in an animal model of hypertensive heart disease.
Purpose of the Study:
- To determine if sacubitril/valsartan (SV) treatment reduces the susceptibility to ventricular arrhythmia in spontaneously hypertensive rats (SHRs).
- To investigate the underlying mechanisms, including effects on cardiac geometry, diastolic function, electrical remodeling, and KCNN2 expression.
Main Methods:
- Spontaneous hypertensive rats (SHRs) and Wistar Kyoto rats were used.
- SHRs were treated with valsartan or sacubitril/valsartan (SV).
- Ventricular tachyarrhythmia induction, in vitro optical mapping, and analysis of KCNN2 levels in cardiac tissue were performed.
Main Results:
- SV treatment significantly improved cardiac geometry and diastolic dysfunction in SHRs compared to untreated SHRs.
- The incidence of induced ventricular tachycardia and fibrillation was significantly reduced in SV-treated SHRs.
- SV treatment normalized prolonged action potential duration and reduced the maximum slope of action potential duration restitution, associated with decreased KCNN2 expression.
Conclusions:
- Sacubitril/valsartan (SV) treatment in spontaneously hypertensive rats (SHRs) attenuates ventricular arrhythmogenesis.
- The anti-arrhythmic effects are linked to KCNN2-associated electrical remodeling, stabilizing electrical dynamics.
- SV demonstrates potential in managing hypertensive heart disease by improving electrical stability and reducing arrhythmia susceptibility.
Aims:
Hypertension is a significant risk for the development of left ventricular hypertrophy, diastolic dysfunction, followed by heart failure and sudden cardiac death. While therapy with sacubitril/valsartan (SV) reduces the risk of sudden cardiac death in patients with heart failure and systolic dysfunction, the effect on those with diastolic dysfunction remains unclear. We hypothesized that, in the animal model of hypertensive heart disease, treatment with SV reduces the susceptibility to ventricular arrhythmia.
Methods And Results:
Young adult female spontaneous hypertensive rats (SHRs) were randomly separated into three groups, which were SHRs, SHRs treated with valsartan, and SHRs treated with SV. In addition, the age-matched and weight-matched Wistar Kyoto rats were considered as controls, and there were 12 rats in each group. In vivo ventricular tachyarrhythmia induction and in vitro optical mapping were used to measure the inducibility of ventricular arrhythmias and to characterize the dynamic properties of electrical propagation. The level of small-conductance Ca2+ -activated potassium channel type 2 (KCNN2) was analysed in cardiac tissue. Compared with SHR with left ventricular hypertrophy, treatment with SV significantly improved cardiac geometry (relative wall thickness, 0.68 ± 0.11 vs. 0.76 ± 0.13, P < 0.05) and diastolic dysfunction (isovolumetric relaxation time, 59.4 ± 3.2 vs. 70.5 ± 4.2 ms, P < 0.05; deceleration time of mitral E wave, 46 ± 4.8 vs. 42 ± 3.8, P < 0.05). The incidence of induced ventricular arrhythmia was significantly reduced in SHR treated with SV compared with SHR (ventricular tachycardia, 1.14 ± 0.32 vs. 2.91 ± 0.5 episodes per 10 stimuli, P < 0.001; ventricular fibrillation, 1.72 ± 0.31 vs. 5.81 ± 0.42 episodes per 10 stimuli, P < 0.001). The prolonged action potential duration (APD) and increase of the maximum slope of APD restitution were observed in SHR, while the treatment of SV improved the arrhythmogeneity (APD, 37.12 ± 6.18 vs. 92.41 ± 10.71 ms at 250 ms pacing cycle length, P < 0.001; max slope 0.29 ± 0.01 vs. 1.48 ± 0.04, P < 0.001). These effects were strongly associated with down-regulation of KCNN2 (0.38 ± 0.07 vs. 0.74 ± 0.12 ng/ml, P < 0.001). The treatment of SV also decreased the level of N-terminal pro-B-type natriuretic peptide, cardiac bridging integrator-1, and intramyocardial fibrosis of SHR.
Conclusions:
In conclusion, synergistic blockade of the neprilysin and the renin-angiotensin system by SV in SHRs results in KCNN2-associated electrical remodelling in ventricle, which stabilizes electrical dynamics and attenuates arrhythmogenesis.
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