Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice.
OBJECTIVE
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.


METHODS
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.


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
Selective heart rate reduction with ivabradine limits cardiac dysfunction and prevents the renovascular and cerebrovascular endothelial dysfunction associated with dyslipidaemia.
Drouin
A
A
Montreal Heart Institute, Research Center, Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada.
Gendron
M-E
ME
Thorin
E
E
Gillis
M-A
MA
Mahlberg-Gaudin
F
F
Tardif
J-C
JC
D000109:Acetylcholine; D000818:Animals; D053299:Apolipoprotein B-100 / Q000235:genetics; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism; D050171:Dyslipidemias / Q000150:complications; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D000077550:Ivabradine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012077:Renal Artery / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
D053299:Apolipoprotein B-100; D001552:Benzazepines; D002316:Cardiotonic Agents; D000077550:Ivabradine; D000109:Acetylcholine