Progressive left ventricular hypertrophy after withdrawal of long-term ACE inhibition following experimental myocardial infarction.
BACKGROUND
Although discontinuation of chronic ACE inhibitor (ACEi) therapy after myocardial infarction (MI) is common in clinical practice, some clinical studies reported an increased incidence of ischemia-related events after withdrawal. To further address this issue, we assessed hemodynamic, neurohormonal and vascular consequences of withdrawing long-term ACEi treatment after experimental MI.


METHODS
Rats were subjected to coronary ligation to induce MI, and received quinapril (15 mg/kg/day) from 2 weeks to 14 months post-MI. Subsequently, surviving rats were randomized to sacrifice at 0, 4, and 6 weeks after ACEi withdrawal. Rats were studied for signs of heart failure, hemodynamics and cardiac function, neurohormones, and vascular edothelial function.


RESULTS
After discontinuation of ACEi treatment, plasma aldosterone levels increased between 0-4 weeks without further increment thereafter, suggesting persistent RAAS activation. Acetylcholine-induced aortic relaxation was impaired at 4 and 6 weeks, indicating rapid and sustained development of endothelial vasodilator dysfunction after withdrawal. Moreover, 24% of the rats developed heart failure signs (edema, dyspnea), and 3 rats died, all within 4 weeks after withdrawal. Significantly increased N-ANP levels and lung weights at 4, but not at 6 weeks suggest a transient volume overload. Finally, LV/body weight ratios significantly increased between 0-4 as well as 4-6 weeks, indicating progressive LV hypertrophy.


CONCLUSIONS
The observed alterations after withdrawing long-term post-MI quinapril treatment in the present study may account for an increased risk for ischemic events. Thus, our findings highlight the potentially harmful effects associated with abrupt discontinuation of long-term post-MI ACE inhibition, and imply careful clinical consideration in this matter.
Westendorp
Bart
B
Department of Clinical Pharmacology, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. b.westendorp@med.rug.nl
Schoemaker
Regien G
RG
Buikema
Hendrik
H
Boomsma
Frans
F
van Veldhuisen
Dirk J
DJ
van Gilst
Wiek H
WH
D000450:Aldosterone / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D000077583:Quinapril; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D013375:Substance Withdrawal Syndrome; D044005:Tetrahydroisoquinolines / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D044005:Tetrahydroisoquinolines; D000450:Aldosterone; D012083:Renin; D000077583:Quinapril