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5THE ROLE OF GALECTIN-3 AND ADHERENCE TO THERAPY IN THE DEVELOPMENT OF CARDIOVASCULAR COMPLICATIONS IN LONG-TERM MONITORING OF PATIENTS WITH MYOCARDIAL INFARCTION OF THE RIGHT VENTRICLE ON THE BACKGROUND OF THE Q-MYOCARDIAL INFARCTION OF
THE LEFT VENTRICLE POSTERIOR WALL
Lozova T.A.
PhD, cardiologist of Clinical Hospital #1, Sumy, Ukraine
Tseluyko V.Y.
MD, PhD, Professor, Head of Cardiology and Functional Diagnostics Department Academy of Postgraduate Education, Kharkiv, Ukraine
Dominas V.M
Head of Clinical Hospital #1, Sumy, Ukraine
ABSTRACT
Study is devoted to the identification of risk factors for adverse cardiovascular events (ACVE) in long-term follow-up of patients with right ventricular myocardial infarction (RV MI) on the background of the Q-MI of the left ventricle posterior wall. The independent factors, associated with development of ACVE-endpoint were low adherence to therapy secondary prevention medications: ACE inhibitors / RBA, statins, clopidogrel, and low frequency of use of maximum doses of statins. It has been proved the prognostic significance of 6-month Gal-3 level as a predictor of CV-complications, such as the UA, stroke, re-MI, and CV-death for 30.6 months follow-up in patients with RV MI.
Keywords: galectin-3, adherence to therapy, myocardial infarction of the right ventricle, complications, predictors.
Introduction.
The 2013 Global Burden of Disease Study estimated that almost 30% of all deaths worldwide were caused by cardiovascular disease (CVD) [7]. Among CVD an acute myocardial infarction (MI) remains a leading cause of morbidity and mortality, and is considered to be one of the most important medical and social problems of the 21st century [2]. MI is the cause of approximately three-quarters of all coronary artery disease (CAD) death and accounts for about a half of all CAD hospital admissions [19]. The registers data have shown the highest rate of CV-readmissions and mortality was occurred during the first year after acute MI, and it has reminded high in the subsequent [1, 2].
Major population studies on the prognosis of patients with MI, which formed the basis of clinical recommendations, were made taking into account the defeat of the left ventricle (LV), in this context the degree of individual risk in patients with MI of the right ventricle (RV) is still the subject of discussion [9].
RV MI is frequently caused by proximal occlusion of the dominant right coronary artery. It has been estimated that 30-50% of all acute MI of the left ventricle (LV) posterior wall (PW) is associated with RV MI. The relationship between RV involvement in acute MI and the increase in-hospital mortality and high risk life-threatening complication in long-term follow-up has been established [13]. However, the degree of this increased risk has been still debated. In this context the studies to identify additional factors that stratify the risk of life-threatening complications and death in patients after RV MI, do not lose their relevance.
Currently the research of laboratory markers plays impotent role in objectivisation for the clinical data, risk stratification, and the assessment of prognosis and therapeutic effects for patients with MI [17]. In recent years the subject of active study was diagnostic, clinical and prognostic value of galectin-3 (Gal-3). Gal-3 is a beta-galactoside-binding lectin expressed by
activated macrophages and involved in numerous pathological processes, including inflammation, fibrosis, apoptosis and tumor growth, which underlie the progression of heart failure (HF) [11, 12]. Some clinical studies confirmed the role of Gal-3 in the development of adverse cardiovascular events (ACVE) in patients with acute coronary syndrome (ACS) [6, 21]. However, the prognostic significance of Gal-3 does not appear in patients with RV MI.
Long-term survival of patients after MI in addition to clinical factors is directly dependent on adherence to cardiovascular therapy [4, 8]. Population studies have shown less than 50% of patients with CAD adhere to the prescribed therapy and it has serious implications in the increase of morbidity and mortality [5]. The consequences of non-adherence to evidence-based therapy in patients after MI are especially profound, but this problem has not yet been studied in subgroup patients after RV MI.
Objective: To evaluate the role of the Gal-3 and medicine adherence with the development of adverse cardiovascular events (ACVE) in the long term follow-up in patients with RV MI on the background Q-MI LV PW.
Materials and methods.
The study included 155 patients with right ventricle MI on the background of Q-MI LV PW who were admitted to the Sumy Clinical Hospital #1 from December 2010 to June 2014. The patients' age was from 34 to 83 years (64.11 ± 0.78 years), overall were 103 (66.5%) men and 52 (33.5%) women.
Acute MI was diagnosed on the basis of clinical, laboratory and instrumental examination in accordance with the recommendations of the European Society of Cardiology (2012). [20] Acute Q-PWLV MI was established by at least 1-mm ST segment elevation in at least two contiguous leads on the baseline electrocardiogram: II, III and aVF, and confirmed by significantly increased concentration of Troponin T. Right ventricular myocardial involvement was diagnosed if there
was at least 1-mm ST segment elevation in the right precordial leads V3R-V4R, within 12 h of symptom onset [20].
The Gal-3 were determined on the 2nd day of MI and in the 6th months after RV MI by ELISA using a novel optimized enzyme-linked immunosorbent assay kit (Vienna, Austria).
The adherence to evidence-based medications, such as beta-blockers, statins, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB), acetylsalicylic acid (ASA) and clopidogrel have been analyzed for the 6th month and the 30th month after RV MI by interviewing the patients or their relatives [16, 20].
The period of follow-up was 30.6 ± 4.5 months. We evaluated a combined endpoint that included CV-death, unstable angina (UA), re-MI and stroke. These ACVE have been occurring in 62 (40%) patients during 30 months. Patients with ACVE were included in the 1st group. The 2nd group was performed by the patients without CV-complications.
Statistical Analysis.
Descriptive variables are presented as mean ± standard deviation (SD) and categorical data are presented as frequencies and percentages. Differences in characteristics between patient groups were estimated using the Student t-test and x2-test. Multivariate stepwise regression analysis was used to evaluate the prognostic role of some indicators. For all analyzes the differences were considered statistically significant at p <0.05.
Results and Discussion.
For 30.6-month follow-up the combined study endpoint
has been achieved in 62 (40%) patients: 50 (32.2%) re-hospitalization for UA, 15 (9.6%) cases of re-MI, stroke - in 9 (5.8%) patients, 16 people died (10.3%) on the CV-reasons. The baseline characteristics for each RV MI gropes are summarized in Table 1.
At the time of inclusion in the study the groups of patients did not differ by gender and anthropometric indices (BMI). Patients with complicated post-MI were older (67.7 ± 0.95 years, p = 0.0001), they had a longer history of CAD (2.3 times, p <0.0001) and a significantly greater number of previous stroke (24.2%, p = 0.0145) and MI (3 times, p = 0.002). The proportion of diabetes mellitus (DM) (38.7%, p = 0.0156) and arterial hypertension (AH) (91.9%, p = 0.026) was significantly higher in the 1st group (Table 1).
Percutaneous coronary interventions (PCI) in acute MI have not been conducted because of the lack of technical capacity.
Analysis of drug therapy in acute MI has shown that in the 1st group patients significantly less used thrombolytic therapy (TLT) (p = 0.0067), fewer patients received maximum doses of statins (rosuvastatin - 40 mg, atorvastatin - 80 mg) (p = 0.00001), but inotropic agents (p = 0.041) and nitrates (p = 0.0217) were used more often. There were not, however, significant differences in the frequency of the use of low-molecular-weight heparin (LMWH), fondaparinux, beta-blockers, ACE inhibitors / ARB, ASA and clopidogrel in both patients groups (Table 1).
Table 1
Baseline clinical characteristics and therapy of patients with RV MI
Variable Mean± SD or n (%) x2 , P
Patients with ACVE n=62 Patients without ACVE n=93
Female (n, %) 24 (38.7%) 28 (30.1%) 1.23; p=0.27
Male (n, %) 38 (61.3%) 65 (69.9%) 1.23; p=0.27
Age, years 67.7 ± 0.95 61.72 ± 1.07 p=0.0001
BMI, kg/m2 30.23 ± 0.65 29.02 ± 0.51 p=0.38
History of CAD, years 7.22 ± 0.77 3.08 ± 0.4 p=0.000003
Diabetes mellitus 24 (38.7%) 17 (18.3%) 5.85; p=0.0156
Arterial hypertension 57 (91.9%) 74 (79.5%) 4.87; p=0.0026
Previous MI 18 (29%) 6 (6.5%) 8.97; p=0.002
Previous stroke 15 (24.2%) 7 (7.5%) 5,98; p=0.0145
TLT 19 (30.6%) 49 (52.7%) c2=7.34; p=0.0067
LMWH 12 (19.3%) 28 (30.1%) 2.25; p=0.1339
Fondaparinux 50 (80.6%) 65 (69.9%) 3.25; p=0.1876
Inotropic agents 16 (25.8%) 12 (12.9%) 4.18; p=0,041
Beta-blockers 56 (90.3%) 86 (92.5%) 0.89; p=0.243
ACE inhibitors / ARB 59 (95.1%) 89 (95.7%) 0.22; p=0.542
Statin 61 (98.4%) 93 (100%) 1.51; p=0.219
Statin, maximum dose 11 (17.7%) 64 (68.8%) 34.51; p=0.00001
ASA 60 (96.7%) 91 (97.8%) 0.171; p=0.937
Clopidogrel 61 (98.4%) 92 (98.9%) 0.878; p=0.9164
Nitrates 18 (29.0%) 13 (14.0%) 5.27; p=0.0217
At the time of hospital discharge, all patients were being given a standard drug therapy in accordance with 2013 ESC guidelines on the management of stable coronary artery disease (2013) [16].
Adherence to post-MI secondary prevention medications significantly decreased (p <0.05) in both groups patients in 6-months follow-up after RV MI. However, in the 1st group there was a significant decrease in the frequency of receiving ACE inhibitors / ARB (p = 0.002), clopidogrel (p = 0.00001), and statins (p = 0.00001) compared with 2nd group patients. Non-adherence of ASA and beta-blockers increased in all patients compared to the initial assignments (p <0.05), even though the marked differences among the groups have not been achieved.
Treatment of post-MI patients assumes the use of dual antiplatelet therapy for a year [20]. Analysis of the survey data of patients has shown that, despite of the recommendations, within 12 months after RV MI clopidogrel received 44.1% of patients in the 2nd group and 19.4% of patients in the group of complicated follow-up (p = 0.0015).
At the end of the observation period, surgical revascularization was performed in 43.8% of patients after RV MI. Despite of the presence of ACVE in the 1st group of patients the frequency of PCI (p = 0.0001), and coronary
The 2nd group patients were much more often recommended maximum doses of statins (p = 0.00001), but otherwise, the frequency of the use of basic-evidence drugs did not significantly differ (Table 2).
artery bypass grafting (CABG) (p = 0.012) were significantly lower. Adherence to medication significantly decreased in both groups compared with baseline values (p<0.05) and a period of 6 months (p<0.05) (Table 2).
There was no significant difference in the number of patients treated with ACE inhibitors / ARB and beta-blockers at the moment 30.6 month. However, among the survivors of the 1st group adherence to statins was 8.1%, ASA - 38.7%, which was significantly lower than those in patients of the 2nd group, which statins were using by 34.4% of patients (p = 0.0002), and ASA - by 56.9% patients (p = 0.00011).
Recent studies have shown less half of post-MI patients adhering to their base-evidence medications within 1 year after MI, and the largest decrement of non-adherence occurring in the first 6 months after MI, which is confirmed in our study [4]. Poor adherence to therapy in patients after MI accompanied by a significant increase in CV-mortality [3]. According to the results of stepwise regression analysis the most significant factors in the development of ACVE in patients after MI RV were revealed the low frequency of use of maximal doses of
Table 2
Adherence to the drug therapy of patients after RV MI in the dynamic of monitoring (30.6 ± 4.5 months), (n, %).
Variable Patients with ACVE n=62 Patients without ACVE n=93 x2 » P
The therapy at the moment of hospital discharge
Beta-blockers 58 (93.5%) 90 (96.8%) 0.90; p=0.343
ACE inhibitors / ARB 60 (96.7%) 89 (95.7%) 0.12; p=0.734
Statin 61 (98.4%) 93 (100%) 1.51; p=0.219
Statin, maximum dose 13 (20.9%) 66 (70.1%) 37.21 p=0.00001
ASA 60 (96.7%) 91 (97.8%) 0.171; p=0.937
Clopidogrel 61 (98.4%) 92 (98.9%) 0.878; p=0.9164
6-month follow-up
Beta-blockers 50 (80.6%)* 78 (84.9%)* 0.27; p=0.604
ACE inhibitors / ARB 43 (69.4%)* 83 (89.2%)* 9.68; p=0.002
Clopidogrel 27 (43.5%)* 71 (76.3%)* 17.21; p=0.00001
Clopidogrel in 12 month 12 (19.4%)*A 41 (44.1%)*A 10.11; p=0.0015
Statin 14 (22.6%)* 67 (72.0%)* 36.48; p=0.00001
ASA 54 (87.1%)* 86 (92.4%)* 0.692; p=0.783
30.6-month follow-up
Beta-blockers 31 (50%)*A 47 (50.5%)*A 0.01; p=0.948
ACE inhibitors / ARB 37 (59.7%)*A 65 (69.9%)*A 1.73; p=0.189
Statin 5 (8.1%)*A 32 (34.4%)*A 14.21; p=0.0002
ASA 24 (38.7%)*A 53 (56.9%)*A 4.268; p=0.00011
Surgical revascularization
CABG 5 (8.1%) 22 (23.7%) 6.29; p=0.012
PCI 6 (9.7%) 35 (37.6%) 14.95; p=0.0001
* Significant differences compared with baseline (p <0.05) A Significant differences compared with 6-months follow-up (p <0.05)
statins (10.18%, p = 0.0001) in the acute period RV MI, early (before 6 months) discontinuation of clopidogrel (8.48%, p = 0.021) and statins (7.21%, p = 0.037). These data correspond to the results of clinical trials, which had shown an increased risk of re-MI and CV-death in post-MI patients from non-adherence of clopidogrel and statins [5], (Table 3).
The disorders of hemodinamics and acute decompensation
of heart failure had not been considered as an integral component of the combined endpoint. Perhaps this explains the lack of statistical significant effect on the prognosis of patients after RV MI low adherence of beta-blockers (2.97%, p = 0.23) and ACE inhibitors / RBA (2.28%, p = 0.31) in this study (Table 3).
Table 3
The effect of adherence to therapy on the development of the CV-endpoint for 30.6 ± 4.5 follow-up in patients after RV MI on
the background of Q-MI LVPW
Variable Beta B The degree of influence, % P
Clopidogrel, 6 months -0.20 -0.19 8.48 0.021
Statin, maximum dose -0.24 -0.23 10.18 0.00014
Statin, 6 months -0.17 -0.16 7.21 0.037
Beta-blockers, 6 month 0.07 0.09 2.97 0.23
ACE inhibitors / ARB, 6 months 0.09 0.07 2.28 0.31
PCI -0.19 -0.16 3.44 0.097
CABG 0.26 -0.19 2.75 0.081
The results of our study have not shown significant effect of PCI and CABG on long-term prognosis in patients after RV MI, however, they have demonstrated the importance of non-adherence of secondary prevention drug medications in the development of ACVE for 30.6 month follow-up.
It has been proved in patients after MI that for each 10% increase in adherence of secondary prevention drugs, an additional can be prevented 6.7% fatal and non-fatal CV events [3].
The results of meta-analysis of 21 studies, 46 847 patients, have shown a close relationship between adherence to based evidence therapy and about the 50% decreased the risk of mortality [18]. The influence of adherence of "proved beneficial drug" in improving prognosis is so high that, according to S.H. Simpson, D.T. Eurich, S.R. Majumdar et al. (2006), it can be considered as a "surrogate marker for overall healthy behavior." [18].
Considering the role Gal-3 as the mediator of fibrosis, apoptosis and a potential marker of adverse cardiac remodeling [11, 14], it has been found the involvement of Gal-3 in the development and progression of HF and increasing risk of CV-
Dynamics of galectin-3 in the
outcomes after atherothrombosis [10, 15].
The mean level of Gal-3 on the 2nd day of acute RV MI in the examined patients was 31.48 ± 0.79 ng/ml. In the 1st group the biseline concentrations of Gal-3 were significantly higher (35.61 ± 0.64 ng/ml) compared to the 2nd group patients without ACVE in 30.6 month follow-up (26.83 ± 0 72 ng/ml, p <0.0001).
In a period of 6 months after RV MI the mean concentration of Gal-3 (29.28 ± 1.77 ng/ml) in the common group was lower than baseline, but not significantly different (p = 0.262).
In the group of patients with complicated post-infarction period, the mean level of Gal-3 (38.61 ± 2.04 ng / ml, p <0.0001) was significantly higher than the rate of patients in the 2nd group (18.8 ± 0.53 ng/ml) (Table 4.). In the dynamics of observation, it has been found that Gal-3 levels in patients with ACVE in follow-up in 6 months have increased slightly (38.61 ± 2.04 ng / ml, p = 0.17). At the same time in the 2nd group patients without complications the Gal-3 concentration has significantly decreased (18.8 ± 0.53 ng / ml, p <0.0001) (Table. 3).
Table 4
patients, (Mean ± SD)
Variable 1st grope n=62 2nd grope n=93 P
Gal-3, ng/ml, the 2nd day RV 35.61 ± 0,64 26.83 ± 0,72 <0,0001
Gal-3, ng/ml, the 6 th month 38.61 ± 2,04 18.8 ± 0,53* <0,0001
* Significant differences compared with baseline (p <0.0001)
Considering the higher compliance to drug therapy in the 2nd group patients, the study had been assessed the possible impact of therapy on the level of galectin-3 in 6 months after
RV MI. As the result of stepwise regression analysis, it has been found that the independent association with increased 6-month Gal-3 levels were non-adherence of statins (4.8%, p =
0.001478) and Clopidogrel (4.58%, p = 0.048061), the lack of use RV MI and insufficient conduct of PCI (6.11%, p = 0.013476) of thrombolytic therapy (4.66%, p = 0.00469) in acute period during the first 6 months after RV MI (Table 5).
Table 5
The effect of therapy on the level of Gal-3 in 6 months after RV MI
Variable Beta В The degree of influence, % Р
Clopidogrel, before 6th month -0.21 -3.07 4.58 0.048061
Statin, before 6th month -0.22 -19.63 4.8 0.001478
TLT -0.19 -2.81 4.66 0.004690
ACE inhibitors / ARB, before 6 th month -0.12 -1.93 2.62 0.097188
PCI, before 6th month -0.28 -5.39 6.11 0.013476
Beta-blockers, before 6th month -0.12 -2.23 2.42 0.103458
CABG, before 6th month -0.21 -3.36 4.08 0.0955837
Stepwise multivariate regression analysis has demonstrated that the Gal-3 level in 6 months after RV MI had been significantly and independently associated with the development of ACVE:
Recent studies have proved that levels of Gal-3 reflect the basic mechanisms of atherosclerosis and development of plaque [15]. It has shown the relationship between the increased Gal-3 levels and the number of arteries affected by atherosclerosis [6]. Moreover, the increase of Gal-3 concentration can be used as a marker of plaque rupture, and associated with development of ACS, and clinical complications in patients of atherothrombosis [6, 15].
Thus the combining of the measured Gal-3 with the clinical factors in patients with RV MI on the background of the posterior Q-MI may have actuality as an additional marker of diagnosis, assessment of the risk of ACVE in long-term follow-up and potentially therapeutic management.
Conclusions.
1. It has been proved the prognostic significance of 6-month Gal-3 level as a predictor of the UA (12.5%, p = 0.000028), stroke (7.9%, p = 0.000514), re-MI (6.5%, p = 0.002259), and CV-death (14.1%, p = 0.0000001) for 30.6 months follow-up in patients with RV MI.
2. According to the results multivariate regression analyses the increased of 6-month Gal-3 levels was associated with non-adherence of statins (4.8%, p = 0.001478) and clopidogrel (4.58%, p = 0.048061), lack of use of thrombolytic therapy (4.66%, p = 0.00469) in acute period RV MI and insufficient conduct of PCI (6.11%, p = 0.013476) during the first 6 months after RV MI.
3. Low adherence to therapy based-evidence groups of
re-MI (6.5%, p = 0.002259), UA (12, 5%, p = 0.000028), stroke (7.9%, p = 0.000514) and CV-death (14.1%, p = 0.0000001) for 30-month observation period (Table 6).
drugs: ACE inhibitors / RBA (69.4-59.7%), statins (22.6-8.1%), clopidogrel (43.5-19.4%) is an independent a factor associated with the development of ACVE in patients with RV MI on a background of Q-MI PWLV.
4. As a result of stepwise regression analysis the independent factors, associated with development of CV-endpoint were low frequency of use of maximum doses of statins (10.18%), early discontinuation of clopidogrel (8.48%), and statins (7.21%) in a 6 month period after MI RV.
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Table 6. The relationship between the Gal-3 level in 6th month after RV MI and ACVE
Variable Beta В The degree of influence, % P
UA 0,34 9.77 12.5 0.000028
CV-deth 0.43 15.65 14.1 0.0000001
Re-MI 0.19 7.5 6.5 0.002259
Stroke 0.24 12.39 7.9 0.000514
History of CAD 0.11 0.23 3.6 0.106
Age 0.08 0.29 2.11 0.33
AH 0.19 0.27 2.18 0.14
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