The effectiveness of the renin-angiotensin system blockers in patients with coronary artery disease after surgery coronary artery bypass grafting
Introduction. Today it is clear that the renin-angiotensin-aldosterone system (RAAS) is not only the most important regulatory system, but also plays a central role in a wide range of pathological processes in different tissues and organs.  Changes in the RAAS (both activation and suppression) identified in more than 30 nosology and syndromes. [1,2]
During and after application of the artificial circulation RAAS is hyperactivated in order to the changes in the balance of angiotensin II / bradykinin, what leads to endothelial dysfunction. The angiotensin II activities are also associated with numerous adverse cardiovascular effects, including inflammation, thrombosis, apoptosis, atherosclerosis, fibrosis and plaque rupture. 
There is a proven efficacy of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in ambulatory patients with ischemic heart disease, but efficiency of their use in patients undergoing coronary artery bypass grafting is unstable and inconsistent. [2,3]
Data of International Multicenter Study on Perioperative Ischemia (McSPI)-Epidemiology II (EPI-II), published in 2012, showed that the perioperative use of ACE inhibitors in patients after coronary artery bypass grafting (CABG) is associated with prophylactic anti iflamatory and antiplatelet potential, which can provide further protection from cerebrovascular and renal adverse events [1,2]. More over, the use of ACE inhibitors in the early postoperative period may be associated with a significant improvement in cardiovascular and renal outcomes. Canceling ACE inhibitors after surgery is associated with poor prognosis of non-fatal outcomes.
Materials and methods. At the Department of Cardiology and Functional Diagnostics of P.L. Shupyk National Medical Academy of Postgraduate Education, Kiev, Ukraine, carried out a comprehensive investigation and dynamic monitoring of the 140 patients with ischemic heart disease and postinfarction cardiosclerosis after CABG surgery. CABG was carried out in the CAD surgery Department (leader – A.V.Rudenko) of National Institute of cardiovascular surgery named N.N.Amosov, Kiev, Ukraine.
Patients were examined 7-10 days prior to coronary artery bypass surgery and during following 10 days, 6 and 12 months period after performing surgery.
All patients received a standard therapy for patients with history of ischemic heart disease according to existing recommendations including beta-blockers, ACE inhibitors / ARBs , diuretics, nitrates (if necessary), antiplatelet therapy and statins. [4,5] Patients were divided into 2 groups: the first group (105 patients) received standard therapy and ACE inhibitors (Enalapril, Lisinopril), the second one (35 patients) consisting of patients intolerant to ACE inhibitors (complained of cough occurrence) — received standard treatment and ARBs (Valsartan).
The average age of the patients was 56,49 ± 9,56 years (M ± SD), 118 males (84,2%), 22 female patients (15,7%); 62 of them (44,2%) had a history of hypertension II degree, 95 patients (67,8%) – angina pectoris grade II, 113 patients (80,7%) – heart failure grade IIA. Of all patients had a myocardial infarction (MI) with Q wave — 48 (34,2%).
The criteria for exclusion: hemodynamically significant valvular heart disease, chronic obstructive pulmonary disease, history of myocarditis, permanent or temporary pacing, patients with acute heart failure and implantable cardioverter-defibrillator, atrial fibrillation. During all period of observation with not just holding general clinical examination also it was held dopplerography and ultrasonic scanning (by system Medison SonoAce 9900, Korea). All measurements were performed according to latest recommendations of the American Society of Echocardiography and Ukrainian Association of Cardiology. [6,7,8,9] Software program used for statistical analysis -"Statistics 6.0 for Windows" and Microsoft Excel. Results are presented as mean ± standard deviation (M±SD). Confidence intervals were within 95%, a difference of investigated parameters were considered significant at p 0,05.
Results and discussion. Indicators of myocardial function, left ventricular remodeling and central hemodynamics did not differ significantly before surgery within two groups . Ejection fraction (EF) was measured in 7-10 days since CABG: it was 45,29 ± 10,14 in an ACE group and 47,50 ± 11,59 in ARBs group. Immediately after CABG (7-10 days) clinically significant improvement in performance in the two groups were not observed, although in group 2 receiving BRAІІ, compared with a group of ACE inhibitors significantly decreased left atrial (LA) index (2,13 ± 0,31 vs. 2,23 ± 0,18, p = 0,021), EDD (3,07 ± 0,41 vs. 2,79 ± 0,45, p 0,0001), ESD (2,43 ± 0,47 vs. 2,14 ± 0,46, p 0,0001) and EDV (118,67 ± 39,62 vs. 80, 87 ± 23,72, p 0,0001). Left ventricular ejection fraction (LVEF) in the ACE group postoperatively remained significantly lower in comparison with the group BRAII (41,8 ± 12,78 vs. 47,50 ± 11,59, p = 0.021). None of this suggests a significant improvement in myocardial function and central hemodynamics after the surgery.
Central hemodynamics, diastolic function and preload were not significantly changed.
Just after 6 months in the ACE inhibitor group, LA diameter index significantly decreased compared with postoperative data (2,14 ± 0,3 vs. 2,23 ± 0,18, p = 0,009), and the same was occurred with E/Em (8, 34 ± 4,1 vs. 10,44 ± 3,3, p = 0,0001), which is the most sensitive indicator of left ventricle preload. On the other hand, after six months this group tended to a significant increase of EDV (91,5 ± 27,68 vs. 80,87 ± 23,72, p = 0,0031) and ESV (53,29 ± 23,66 vs . 46,58 ± 21,0, p = 0,031) at a constant LVEF (43,8 ± 11,4 vs. 41,8 ± 12,78, p = 0,23), which however remained lower than preoperative values.
Moreover the ACE inhibitor group showed no improvement of other parameters of LV diastolic function. Also had a significantly lower down time early diastolic flow left ventricular DTE (161,9 ± 44,7 vs. 177,0 ± 43,08, p = 0.014), although isolated index may not be indicative of the inpairment of the central hemodynamics. A similar pattern persisted 12 months after CABG.
In the ARB group after 6 months since CABG, compared with postoperative data, the vast majority of indicators of myocardial function, remodeling and left ventricular preload did not change significantly, although there was a decrease of LV EDD (2,28 ± 0,36 vs. 2,81 ± 0,45, p 0,0001) isolatedly. However 12 months after CABG in this group were recorded significant improvements in most indicators of remodeling, central hemodynamics and left ventricular preload: reducing EDD (2,55 ± 0,28 vs. 2,81 ± 0,45 , p = 0,0055) at constant volume and ejection fraction of LV, transformation of transmitral LV filling graphics from pseudonormal to impaired relaxation according to speed ratio E / A (0,77 ± 0,35 vs. 1,49 ± 0,87, p 0,0001), reliable growth of deceleration time of early-diastolic flow DTE (183,75 ± 49,26 vs. 155,62 ± 47,88, p = 0,019), which, together with a significant reduction of E / Em (8,0 ± 2,5 vs. 10,65 ± 5,49, p = 0,019) and
E / Vp (1,75 ± 0,35 vs. 2,32 ± 0,97, p = 0,0019 ) indicates the improvement of myocardial function and reduced left ventricular preload in conditions of a moderately reduced global left ventricular contractility (EF in all patients in both groups during the year after CABG was not significantly changed).
When comparing remodeling of the left ventricle, central hemodynamics, diastolic function and left ventricular preload within the groups at 12 months after CABG revealed, that patients treated with ARBs, compared to patients treated with ACE inhibitors, with comparable left ventricular ejection fraction and volumes, were significantly lower LADi (1,9 ± 0,37 vs. 2,16 ± 0,33, p = 0,0002), EDD (2,55 ± 0,28 vs. 2,89 ± 0,5, p = 0,0002) and ESD (1,92 ± 0,33 vs. 2,23 ± 0,47, p = 0,0005), indicating a more pronounced reverse remodeling of the left chmbers at the same LV systolic function. Furthermore, in this group 12 months after CABG observed reversal of diastolic dysfunction stepping from pseudonormalization to impaired relaxation, reduction E / A (0,77 ± 0,35 vs. 1,7 ± 1 , 07, p 0,00001), the growth of DTE (183,75 ± 49,26 vs. 163,19 ± 51,67, p = 0,043) and time isovolumic relaxation IVRT (125,0 ± 38,07 vs. 102 , 82 ± 39,75, p = 0,005) — indicating a significant improvement of LV diastolic function and reduced left atrial pressure, as evidenced by significantly greater reduction in the combined index of left ventricular preload Vp (1,75 ± 0,35 vs. 2,41 ± 0,93, p 0,0001).
Conclusion. The findings lead to the conclusion that after coronary bypass surgery prescribe of RAAS blockers has a positive effect on the remodeling of the left chambers, left ventricular myocardial function and central hemodynamics, leading to the left heart pressure decrease, reducing left ventricular preload and improving its diastolic function with a moderate reduction in systolic function. However, the effects of ACE inhibitors according to Doppler echocardiography in six months after surgical revascularization is moderate in the form of reducing the size and pressure of an LA (with a slight reverse remodeling of the left ventricle) with a tendency to increase its cavity at constant left ventricular ejection fraction and central hemodynamics. At the same time, the receiving ARBs after CABG allows you to get a significant improvement in most indicators of myocardial function of LV remodeling of the left chambers, central hemodynamics in just 12 months after surgical revascularization, however, these positive changes are persistent and significantly higher than those in patients receiving an ACE inhibitor with a moderate reduction of LV systolic function.