To evaluate the effects of δV1-1 treatment in endothelial-dependent vasodilator capacity, lumen area change after bradykinin infusion in the δV1-1-treated group was compared to that of the control group using IVUS analysis. In control pigs, endothelial-dependent vasodilator capacity following bradykinin infusion in infarct-related epicardial coronary arteries was impaired, while in δV1-1-treated pigs, the endothelial-dependent vasodilator capacity was preserved (). Nitroglycerin infusion caused similar vasodilatory responses in both groups, suggesting preserved endothelial-independent vasodilator capacity ().
We have recently demonstrated that administration of a selective δPKC peptide inhibitor, δV1-1, just before reperfusion reduces myocardial infarct size in a porcine model of AMI.(7
) Here, we demonstrate that this δPKC inhibitor preserved the vasodilator capacity in epicardial coronary arteries in this in vivo
porcine model. Because endothelial dysfunction is related to worsened outcomes in AMI patients, this preserved endothelial function may be, in part, responsible for improved clinical outcomes for these patients.
Our data are consistent with other recent studies, which assess endothelial dysfunction after ischemia and reperfusion. In one study, both coronary flow reserve and electron microscopy in a porcine AMI model demonstrated improved microvascular function due to maintenance of open microvessel following δV1-1 treatment (7
). In a second study of middle cerebral artery occlusion, δV1-1 treatment resulted in improved microvascular pathology, a 92% increase in number of patent microvessels and a 26% increase in cerebral blood flow following acute focal ischemia (15
). Together with our study here, examining endothelial cell function in coronary arteries using IVUS, a picture emerges suggesting that increased cardiac injury following ischemia may be due, at last in part, to endothelial cell dysfunction, and that dysfunction can be reduced by inhibiting δPKC.
In 1982, Ku et al.(9
) demonstrated the first evidence of coronary endothelial dysfunction after ischemia and reperfusion, as evidenced by an impaired endothelium-dependent vasodilatation. Endothelial dysfunction occurs early during reperfusion of previously ischemic tissue and may present for an extended time period (4 to 12 weeks) (16
). Endothelial dysfunction facilitates the expression of a pro-thrombotic phenotype, characterized by platelet and neutrophil activation. Even after successful thrombolysis, 7% of patients suffered from re-infarction in recent fibrinolytic trials, which tends to be associated with poor clinical outcomes (19
). Although catheter-based mechanical reperfusion strategies result in improved clinical outcome over pharmacological reperfusion strategies (20
), fatal or non-fatal myocardial (re)infarction still occurs with more frequency in AMI patients than in patients with stable angina (21
). Superimposed on the inherent systemic vulnerability (hyper-coagulability, inflammatory state) in AMI patients, endothelial dysfunction in coronary arteries is likely to play a role in the development of further acute coronary events. Therefore, our findings that δPKC inhibition with δV1-1 improves endothelial function may translate to improved patient outcome, if these data are corroborated also in humans.
Endothelial dysfunction may also lead to a reduced production of the endothelium-derived vasodilator, nitric oxide. Since nitric oxide has several anti-atherogenic properties, including inhibition of platelet aggregation and smooth muscle cell proliferation, a dysfunctional endothelium may further contribute to a pro-atherogenic state and plaque instability. In experimental animals, nitric oxide availability is inversely related to disease progression. Thus, post MI endothelial dysfunction, exaggerated by ischemia-reperfusion, may accelerate preexisting atherosclerosis in patients with AMI, leading to future ischemic events. Improved endothelial function by inhibiting δPKC may therefore provide an additional benefit, namely reducing plaque instability.
Although angiography has been the predominant method to define coronary anatomy as well as function in the past 40 years, many studies have challenged the accuracy and reproducibility of this technique (22
). Well known are the effects of contrast agents on heart-myocardial contractility, electrophysiology and coronary blood flow, all of which may interfere with vascular responses (23
). Recently, new and emerging applications for IVUS imaging provide an alternative to angiography. Indeed, continuous in vivo
assessment of lumen area by IVUS without contrast agent injection enables a more accurate and detailed analysis of vascular response and health and therefore may better guide therapeutic protocols.
Impact of the δPKC inhibitor on the vasodilator capacity may differ between animals (juvenile but otherwise healthy pig coronary artery) and humans (diseased coronary artery with preexisting plaque rupture, erosion (25
) and/or dysfunctional endothelium and systemic co-morbid conditions (diabetes, hypercholesterolemia, hypertension and so on). Further clinical investigation is needed to determine whether this novel cardioprotective therapy might improve clinical outcomes in patients with AMI.
In conclusion, in addition to reducing myocardial infarct size in the acute phase, this novel cardioprotective therapy of a selective δPKC inhibitor may further improve long-term outcome in patients with AMI, through the preservation of endothelial function, thereby improving flow through the coronary arteries and preventing new ischemic events.