Clinical efficacy of high-dose glucose-insulin-potassium therapy in acute coronary syndrome without ST-segment elevation

The dissertation is devoted to studying the clinical efficacy of high-dose glucose-insulin-potassium solution (GIKS) infusion in patients with acute coronary syndrome without ST-segment elevation. It examines the pathophysiological and metabolic changes in the myocardium during ischaemia and reperfusion, the mechanisms of reversible contractile dysfunction (stunning, hibernation), and the possibilities of pharmacological cardioprotection. Using clinical, laboratory, echocardiographic parameters, endothelium-dependent vasodilation of the brachial artery, and 24-hour ECG monitoring data, the study investigates the effect of GIKS on the severity of ischaemia, myocardial contractile function, endothelial function, and short-term prognosis. The findings clarify the role of metabolic therapy in the comprehensive management of this category of patients and define indications for its use, taking into account the choice between conservative and invasive strategies.

Relevance of the problem

With the development of interventional cardiology technologies, approaches to the treatment of acute coronary syndrome without ST-segment elevation are increasingly shifting towards surgical methods that provide better outcomes (Tricoci P. et al., 2007). At the same time, even when emergency cardiac surgery is available, cytoprotective influence on the myocardium may be considered as a possible means of further improving treatment outcomes in this category of patients. A relevant aspect of cardioprotection is also the limitation of the adverse effects and risks caused by possible delays in performing emergency endovascular procedures.

High-dose infusion of glucose-insulin-potassium solution (GIKS) is widely known as a method of metabolic therapy in cardiology. A number of experimental studies have demonstrated the protective effect of GIKS against ischaemic and reperfusion injury and the limitation of cardiomyocyte apoptosis within the ischaemic zone (Sack M.N. et al., 2003; Folmes C.D. et al., 2006). Clinical studies of GIKS have been conducted in patients with Q-wave myocardial infarction, with the main criterion for evaluating treatment effectiveness being a reduction in the risk of adverse events during prospective follow-up (Diaz R. et al., 2007). The possibilities of GIKS therapy in the perioperative period of elective cardiac surgery have been studied to a lesser extent (Schipke J.D. et al., 2006). Data on the effect of GIKS on the structural and functional parameters of the cardiovascular system are presented in isolated studies concerning myocardial contractile function in patients with Q-wave myocardial infarction (Yetkin E. et al., 2002).

From a pathogenetic perspective, significant positive clinical effects of GIKS infusion may be assumed in patients with acute coronary syndrome without ST-segment elevation. At the same time, to date the possibilities of using GIKS in this category of patients have practically not been explored.

Aim of the study

To investigate the effect of high-dose glucose-insulin-potassium therapy on the functional parameters of the cardiovascular system, the severity of ischaemia, and short-term prognosis in patients with acute coronary syndrome without ST-segment elevation.

Objectives of the study

1. To assess the tolerability of high-dose glucose-insulin-potassium therapy and its effect on clinical indicators and haemodynamic parameters in patients with acute coronary syndrome without ST-segment elevation.

2. Based on 24-hour ECG monitoring data, to evaluate the effects of high-dose glucose-insulin-potassium therapy on the frequency of ischaemic episodes and clinically significant rhythm disturbances.

3. To determine the effect of high-dose glucose-insulin-potassium therapy on the state of endothelium-dependent vasodilatory mechanisms according to the results of the reactive hyperaemia test in patients with acute coronary syndrome.

4. To investigate the dynamics of local and global contractility of the left ventricular myocardium in patients with acute coronary syndrome without ST-segment elevation during high-dose glucose-insulin-potassium therapy.

5. Based on the results of prospective observation, to evaluate the effect of high-dose glucose-insulin-potassium therapy on the frequency of subsequent adverse events (death, myocardial infarction, unstable angina) over a three-month follow-up period.

Main propositions of the thesis defended

In patients with acute coronary syndrome without ST-segment elevation, 24-hour high-dose glucose-insulin-potassium infusion is a safe means of limiting myocardial injury that preserves myocardial viability within the ischaemic zone.

Glucose-insulin-potassium therapy exerts an anti-ischaemic effect characterised by a reduction in the number of ischaemic episodes, which becomes clinically apparent after a 12-hour infusion. The anti-ischaemic effect of glucose-insulin-potassium therapy does not appear to be associated with improvement of endothelial function.

The addition of glucose-insulin-potassium solution to the standard therapy of acute coronary syndrome without ST-segment elevation contributes to improvement of the clinical state; however, if conservative treatment is continued, it is associated with an increase in the number of adverse coronary events over the subsequent three months.

Scientific novelty

The effectiveness of high-dose glucose-insulin-potassium therapy as an adjunct to standard therapy has been demonstrated as a cardioprotective agent preserving myocardial viability in patients with acute coronary syndrome without ST-segment elevation.

It has been established that glucose-insulin-potassium infusion in patients with acute coronary syndrome without ST-segment elevation is accompanied by a reduction in the number of ischaemic episodes and improvement of myocardial contractile function without a substantial effect on the severity of endothelial dysfunction.

When a conservative treatment strategy is chosen for acute coronary syndrome without ST-segment elevation in patients with areas of regional contractile dysfunction, an association has been demonstrated between the administration of high-dose GIKS therapy and a worsening of the disease prognosis over the subsequent three months.

Practical significance of the work

The results of the study make it possible to recommend glucose-insulin-potassium infusion in patients with acute coronary syndrome without ST-segment elevation when emergency myocardial revascularisation is not performed. This form of therapy exerts an anti-ischaemic effect and leads to improvement of myocardial contractility in patients with pre-existing regional contractile dysfunction of the left ventricle without pronounced manifestations of heart failure.

Performing repeat echocardiographic examination during glucose-insulin-potassium infusion enables early identification of patients with reversible myocardial contractile dysfunction who require a more active medical strategy in order to prevent adverse coronary events in the near term.

Implementation of the work

The materials of the completed study were presented as reports at the II International Conference of Young Medical Scientists (21 February 2008, Kursk) and at the Russian–Norwegian Scientific Symposium "Cardioprotection: Molecular, Pathophysiological and Clinical Aspects" (13 May 2008, Saint Petersburg). Four publications have been produced based on the results of the dissertation.

The results of the study have been implemented into the practical work of the Federal State Institution "V.A. Almazov Federal Centre for Heart, Blood and Endocrinology of Rosmedtechnologies" and into the treatment process of the cardiology department for myocardial infarction patients of the Elizavetinskaya Hospital in Saint Petersburg.

Structure and scope of the dissertation

The dissertation is set out on 139 pages of typescript and consists of an introduction, a literature review, two chapters presenting the results of the author's own research, a discussion, and conclusions. The work is illustrated with 19 tables and 10 figures. The bibliography contains 205 references (7 domestic and 198 foreign authors).