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A Murine Model of Hyperlipidemia-Induced Heart Failure with Preserved Ejection Fraction
Published on: March 29, 2024
Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice
A Drouin1, M-E Gendron, E Thorin
1Montreal Heart Institute, Research Center, Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada.
Insights
High resting heart rate predicts mortality in coronary artery disease. Ivabradine, a heart rate-reducing drug, prevented endothelial dysfunction in dyslipidaemic mice, suggesting a protective effect against vascular damage.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Vascular Biology
Background:
- High resting heart rate is a known predictor of cardiovascular mortality in patients with coronary artery disease.
- Dyslipidaemia is associated with endothelial dysfunction, a precursor to cardiovascular events.
Purpose of the Study:
- To investigate if reducing heart rate with ivabradine can prevent endothelial dysfunction in dyslipidaemic mice.
- To assess the impact of ivabradine on cardiac and vascular function in a dyslipidaemic model.
Main Methods:
- Dyslipidaemic (DL) mice and wild-type (WT) mice were studied over 3 months.
- DL mice were treated with ivabradine, an I(f) current inhibitor, or received no treatment.
- Heart rate and arterial dilation responses to acetylcholine were measured.
Main Results:
- Ivabradine treatment limited the age-associated increase in heart rate in DL mice.
- DL mice exhibited impaired arterial dilation, which was completely prevented by ivabradine.
- Ivabradine reduced elevated left ventricular pressures in DL mice.
Conclusions:
- Selective heart rate reduction with ivabradine mitigates cardiac dysfunction.
- Ivabradine prevents renovascular and cerebrovascular endothelial dysfunction associated with dyslipidaemia.
Background And Purpose:
High resting heart rate is a predictor for total and cardiovascular mortality independent of other risk factors in patients with coronary artery disease. We tested the hypothesis that a reduction of resting heart rate with the cardiac pacemaker I(f) current inhibitor ivabradine prevents the endothelial dysfunction associated with dyslipidaemia.
Experimental Approach:
Three-month-old dyslipidaemic (DL) male mice expressing the human ApoB-100 were assigned or not (DL, n=16), to treatment for 3 months with ivabradine (10 mg kg(-1) d(-1), n=17). Wild-type C57Bl/6 mice (WT, n=15) were used as controls. Heart rate was measured at 3, 4.5 and 6 months. Dilatation to acetylcholine (ACh) of isolated cerebral and renal arteries was investigated at 6 months.
Key Results:
Heart rate remained stable in anaesthetized WT mice, increased (25%, P<0.05) with age in DL mice but was limited (11%, P<0.05) by ivabradine. At 6 months, left ventricular maximal pressure was similar in all groups. The minimal and end-diastolic left ventricular pressures were increased (P<0.05) in DL (10.2+/-1.0 and 18.7+/-1.4 mm Hg) compared to WT (-0.4+/-0.7 and 6.3+/-1.0 mm Hg) and reduced (P<0.05) by ivabradine (4.2+/-1.3 and 11.5+/-1.5 mm Hg). ACh-induced maximal dilatation was impaired (P<0.05) in renal and cerebral arteries isolated from DL compared to WT (56+/-7 versus 83+/-3% in renal arteries; 22+/-2 versus 42+/-2% in cerebral arteries). Ivabradine completely prevented (P<0.05) this dysfunction in renal and cerebral arteries.
Conclusions And Implications:
Selective heart rate reduction with ivabradine limits cardiac dysfunction and prevents the renovascular and cerebrovascular endothelial dysfunction associated with dyslipidaemia.
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