| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ann Thorac Surg 2001;72:553-554
© 2001 The Society of Thoracic Surgeons
a Section of Cardiovascular Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
Lazar and colleagues elegantly demonstrate reduced ventricular irritability, improved regional wall motion, preserved endothelial function, and reduced infarct size following angiotensin-converting enzyme (ACE) inhibition in a porcine model of acutely ischemic myocardium. In a randomized, blinded design, the study incorporated 90 minutes of coronary occlusion, 45 minutes of cardioplegic arrest to stimulate three-vessel surgical revascularization, and then permitted 3 hours of reperfusion to allow infarct determination. Despite the clinical correlation, study design, and relevant end-points, detractors will certainly challenge the conclusions. We should address some of these issues.
It is widely known that ACE inhibitors have multiple actions beyond the reduction of systemic blood pressure and angiotensin II generation. In fact, other enzymes such as tissue-plasminogen activator, chymase, cathepsin G, and tonin can also generate angiotensin II. Through inhibition of kininase II, ACE inhibitors also block degradation of bradykinin and other peptides of the kallikrein-kinin system. Augmented levels of bradykinin stimulate production of nitric oxide, prostaglandin E2, prostacyclin, and, possibly, endothelium-dependent hyperpolarizing factor production. These vasoreactive reagents have well characterized actions, including vasodilatation, inhibition of leukocyte adhesion, and inhibition of smooth muscle proliferation. While all of these actions are viewed as beneficial, other actions of ACE inhibitors may negate the clinical benefits.
Due to the antihypertensive effects of ACE inhibitors, concerns have been raised with their use during cardiopulmonary bypass. Indeed, Boldt and colleagues [1] reported decreased levels of atrial natriuretic peptide, epinephrine, endothelin, and norepinephrine during cardiopulmonary bypass (CPB) following the acute administration of the ACE inhibitor enalaprilat. And Tuman and associates [2] noted an increase in pressor utilization with chronic ACE inhibitor use in 4,301 patients undergoing CPB. However, while pressors were required at the termination of CPB, there was no statistically significant difference in pressor requirement after four hours in the intensive care unit. Further, Pigott and colleagues [3] demonstrated that while ACE inhibitor use was associated with increased pressor requirement, acute termination prior to CPB merely resulted in increased requirements for vasodilators. And Rady and associates [4] demonstrated no significant negative clinical outcome with ACE inhibitor use in 7,775 patients with good ventricular function undergoing CPB. So while one must be cognizant that ACE inhibitors may decrease systemic vascular resistance following CPB, the doses utilized in the study of Lazar and associates did not cause hypotension and clinical experience suggests no deleterious effects.
Since some of the actions of ACE inhibitors are dependent upon prostaglandin production by bradykinin, one may be concerned that aspirin may negate some of the benefits of ACE inhibition in coronary revascularization. Indeed, Hall and colleagues [5] demonstrated that aspirin countered the lowering of systemic vascular resistance by enalapril in a small cohort of heart failure patients. This argument is further supported by the CONSENSUS-II trial, which failed to demonstrate a survival improvement with enalapril after myocardial infarction, and subgroup analysis demonstrated increased mortality with aspirin administration [6, 7]. However, the larger GISSI-3 and ISIS-4 trials did demonstrate a survival benefit with ACE inhibition combined with aspirin following myocardial infarction [8, 9]. And a recent meta-analysis failed to identify a difference in outcome with concomitant aspirin use. So, again, while one must be cognizant that other drugs may counteract the beneficial actions of ACE inhibitors, this may not have clinical implications.
The above notwithstanding, what may be a more interesting discussion is the mechanism of action. One must realize that the ACE inhibitors in the present study were administered after coronary occlusion. Thus, the drug did not have the opportunity to enter the vascular bed until reperfusion. The beneficial actions noted with ACE inhibition must have originated as a systemic phenomenon, and acted on the local level only after revascularization. The fact that HOE 140 partially reversed the actions of quinaprilat suggests augmented bradykinin levels were the mediators.
In conclusion, the findings raised by Lazar and colleagues go beyond the theoretical and suggest further investigation clinically. The QUO VADIS trial [10] provides a starting point, but confirmatory clinical experience is required, and additional clinical scenarios, such as suggested in the present manuscript, should be explored.
References
Related Article
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
