Prognostication of late left ventricular systolic dysfunction in patients with acute coronary syndrome during the acute period

The aim of the study was to create the model of the combination of clinical and echocardiographic determinants during the acute period of acute coronary syndromes for the prognostication of the risk for left ventricular dysfunction after one year. We examined 565 patients with first-time acute coronary syndrome with no recurrence during one-year period. The studied group consisted of 496 patients, and the examined group--of 69 patients. All patients with acute coronary syndrome within the first three days underwent the evaluation of demographic, anamnesis, clinical indicators, risk factors for ischemic heart disease, ECG, and echocardiographic findings for the prognostication of the risk of left ventricular dysfunction after one year. Multiple logistic regression analysis was applied for the identification of independent determinants for the prognostication of left ventricular dysfunction, and three risk groups were identified. The prognostic informative value of the model was verified by comparing the incidence of left ventricular systolic dysfunction in risk groups after one year between the studied and the control groups. RESULTS. After one year, left ventricular systolic dysfunction (left ventricular ejection fraction <40%) in the presence of acute coronary syndrome remained in more than half (65.3%) of patients and returned to normal (left ventricular ejection fraction > or =40%) in one-third of patients (34.7%). Left ventricular systolic function that was normal during the acute period of coronary syndrome remained such in the majority (80.9%) of patients after one year, whereas one-fifth (19.1%) of patients developed left ventricular systolic dysfunction. The mathematical model for the prognostication of systolic dysfunction after one year was composed of the determinants of acute coronary syndrome: left ventricular ejection fraction <40%, anterior localization of Q-wave myocardial infarction, Killip class 3-4, left ventricular pseudo-normal or restrictive diastolic function, and frequent ventricular extrasystoles. The application of our model in the prognostication of late left ventricular systolic dysfunction during the acute period of coronary syndrome showed that the model was reliable, since after one year, the prognosticated left ventricular systolic dysfunction was determined in the majority (84.3%) of patients. The designed mathematical model is simple and is based on standard clinical and echocardiographic findings, and the scoring system allows for the prognostication of the risk for late left ventricular systolic dysfunction in any individual patient. The prognostication of the risk for late left ventricular systolic dysfunction during the acute period of coronary syndrome may help in the planning of treatment and outpatient care in patients with acute coronary syndrome.


Introduction
Left ventricular (LV) systolic dysfunction is a common complication of acute coronary syndrome (ACS).In case of ACS, LV systolic dysfunction may occur during the acute period or later.The greatest risk of LV systolic dysfunction arises from myocardial infarction (MI) -especially recurrent -and complex arrhythmias (1).
In the presence of LV systolic dysfunction occurring during the acute period of MI, most patients (70%) experience heart failure (HF), whereas approximately one-third of patients develop no symptoms of HF (2).According to population studies, LV systolic dysfunc-tion and HF in the presence of MI are detected in 30-40% of patients (3)(4)(5).LV systolic dysfunction occurring during the acute period of ACS may disappear or reduce in 20-30% of patients, whereas in more than one-half of patients it may progress or manifest itself through chronic HF (6).According to the findings of the TRACE study, clinical determinants of HF persisted during the later period in 85% of MI patients with severely impaired LV systolic function, while these determinants disappeared in nearly one-half (40%) of patients with slightly impaired LV systolic function (7).During the last decade, the causes, mechanisms, diagnostic options, and outcomes of LV systolic dysfunction have been sufficiently well studied, but the algorithms and models of the clinical course of LV systolic dysfunction are still under development.
The aim of this study was to design a mathematical model of the combination of clinical and echocardiographic (Echo KG) determinants, whose application would allow for the prognostication of the risk for presence and development of LV systolic dysfunction in ACS patients after one year.

The contingent and the methods of the study
The sample consisted of 565 patients with first-time ACS and with no recurrence of the condition within the period of one year.The patients' age ranged from 22 to 86 years (mean age 59.8±9.5 years).The studied group consisted of 496 patients (96 patients hospitalized for high risk of unstable angina pectoris (UAP) and 400 patients with MI).The examined group in which the prognostic models of the risk of LV systolic dysfunction were tested consisted of 69 patients (10 patients with high risk of UAP and 59 patients with MI).There were no significant differences between the groups concerning patients' age, gender, risk factors, damage to coronary arteries (CA), class of acute HF, or treatment tactics applied.The patients underwent inpatient treatment with platelet antiaggregants, anticoagulants, nitrates, b-blockers, ACE inhibitors, and statins.CA angiography was performed in 376 patients of the studied group and in 60 patients of the examined group.Two hundred eight patients underwent percutaneous transluminal angioplasty, and 130 -coronary artery bypass surgery.The characteristics of the patients in the studied and the examined groups are presented in Table 1.
Demographic factors, anamnesis, clinical findings, risk factors, ECG, and Echo KG findings in all patients were evaluated during the first 3-5 days of ACS and after 1 year.
Myocardial infarction was diagnosed based on the World Health Organization (WHO) recommendations: substernal (angina) pain and its equivalents, indicators of ischemic damage on ECG (changes in Q wave, ST seg- ment, and T wave), and increased levels of cardio-specific enzymes.The diagnosis of unstable angina pectoris was confirmed after the detection of the angina syndrome, the emergence of ischemic changes in the ECG without any increase in the blood levels of cardio-specific enzymes, and in the presence of CA damage detected angiographically.More than two-thirds (75.8%) of patients underwent CA angiography according to the Judkins technique.Significant CA stenosis was evaluated when CA constriction was 70% or more.Risk factors were indicated in the following cases: diabetes mellitus -if indicated in the anamnesis, hypoglycemic medications were used, or glucose concentration in blood plasma exceeded 7.0 mmol/L; arterial hypertension, when arterial blood pressure was 140/90 mmHg or higher, or the patient received antihypertensive medications; overweight, when the body mass index was 25 kg/m 2 or greater, frequent extrasystoles (more than 10 per min).Echocardiographic data were gathered using commercially available second harmonic imaging systems by experienced ultrasonographers, and it was repeated by the same investigator.All examinations were performed according to the criteria presented by the American Society of Echocardiography.All measurements were obtained after calculating the mean value of three consecutive measurements.All subjects underwent the evaluation of LV end-diastolic size, the level of remodeling, LV ejection fraction (EF), LV wall motion index (LV WMI), and the degree of mitral regurgitation.LV EF of <40% was considered to be decreased, and LV EF of ³40% -normal.
LV diastolic dysfunction was evaluated using pulse Doppler from apical four chamber view.The evaluation of the degree of diastolic dysfunction (DD) was the following: the 1st degree -impaired relaxation (E/A<1, deceleration time >240 ms); the 2nd degree -pseudo-norm (E/A <2 ->1, the duration of the reverse "a" wave of pulmonary veins exceed that of the "A" wave); the 3rd degree -restriction (E/A>2, deceleration time <140 ms).Pseudo-normal and restrictive LV diastolic dysfunction was seen as severe LV diastolic dysfunction.

Statistical data analysis
Data collection and processing was performed using the standard software packages -"Microsoft Excel 2000" and "Statistika."Quantitative indicators were evaluated using the following statistical characteristics: mean value and standard deviation.The difference was considered to be statistically significant when P<0.05.
The prognostication of the risk of individual determinants for LV systolic dysfunction after one year was evaluated using odds ratio (OR) and confidence inter-val (CI).The determinants, significant in univariate analysis at a P level of 0.10, were entered in the multiple regression models, and their maximal capability of prognosticating LV dysfunction after 1 year was evaluated.The suitability of the models in patient selection was evaluated using c statistics, where the function was equivalent to the area located under the ROC curve.The model was considered to have good discriminatory power when the c index exceeded 0.8.Based on the value of e b (standardized OR) in the model with the highest discriminatory power, each determinant or its level was evaluated in points, and the total score was calculated from the arithmetical sum of these points.The determinants of the selected model were used to evaluate the total score during the acute period.According to the score, all patients were differentiated into three risk groups for the prognostication of LV systolic dysfunction after 1 year.The risk groups were composed so that the difference in the incidence of LV dysfunction would be the greatest, and the P value of the c 2 -the lowest.After one year, we calculated the incidence of LV systolic dysfunction in each risk group.
The prognostic value of the designed model was verified by comparing the incidence of LV systolic dysfunction in the risk groups after one year between the studied and the examined groups.

The incidence of LV systolic dysfunction among patients with first-time ACS and after one year
During the acute period, LV systolic dysfunction (EF<40%) was detected in 30.3% of patients who experienced ACS for the first time and survived for one year without ACS.
In patients with detected LV systolic dysfunction during the acute period, LV systolic dysfunction after one year persisted in more than one-half (65.3%) and returned to normal in about one-third of patients (34.7%) (Fig. 1).
In patients with normal LV systolic function during the acute period, after a year it remained such in the majority of patients (80.9%), and one-fifth of patients (19.1%) developed LV systolic dysfunction.
Thus, after one year following ACS, the incidence of LV systolic dysfunction increased by 3.2% as compared to the acute period.

The informative value of clinical and echocardiographic determinants of coronary syndrome during the acute period for the prognostication of LV systolic dysfunction after one year
We compared clinical, angiographic, and Echo KG determinants of ACS during the acute period in patients who after one year developed LV systolic dysfunction with the respective determinants of patients in whom LV systolic function after one year remained normal; subsequently, we applied linear logistic regression analysis to determine the odds ratio (OR) of these determinants for the prognostication of LV systolic dysfunction after one year (Table 2).

The models of clinical and echocardiographic determinants of coronary syndrome during the acute period for the prognostication of LV systolic dysfunction after one year
Linear regression analysis was used to select 14 significant determinants during the acute period of ACS, and multiple logistic regression analysis was used to evaluate the informative value of these determinants.The findings showed that seven determinants -Q-wave MI, anterior localization of Q-wave MI, Killip class II-IV, LV EF <40%, severe diastolic dysfunction (pseudo-normal or restrictive), LV WMI >1.5, and frequent ventricular extrasystoles -independently increased the probability of the persistence or development of LV systolic dysfunction after one year.Using these determinants, three models were designed for the prognostication of LV systolic dysfunction after one year (Table 3).Since the models contained different combinations of the determinants, their OR differed: for LV EF <40% OR was 5.13-2.57;for anterior Q-wave MI, 4.26-1.96;the OR for Killip class increased (by 1.9-1.4times) with increasing class; and LV pseudo-normal or restrictive dysfunction increased the probability of the persistence or development of LV systolic dysfunction by 2.4-2.1 times.
The evaluation of the sensitivity and specificity of the models using ROC curve showed that the models were both sensitive and specific (had good discriminatory power) for the prognostication of LV systolic dysfunction after one year.The first model had the best discriminatory power (c=0.855):anterior Q-wave MI, LV EF <40%, severe LV diastolic dysfunction, Killip class III-IV, and frequent ventricular extrasystoles.The discriminatory powers of the second and the third models, compared to that of the first one, were lower but were not statistically significantly different (c=0.852 and 0.837 versus 0.855).*Odds ratio >2.0 (significant informative value).

Table 2. The informative value of clinical and electro-physiological determinants during the acute period of ACS for the prognostication of LV systolic dysfunction after one year (n=496)
The informative value of the independent determinants of the first model, calculated in risk score index, is presented in Table 4.
The total score index for the prognostication of late LV systolic dysfunction varied between 0 and 12 (Table 4).The median score was 3.2 points.In the majority of patients (72.1%), the total score was less than 6 points.The following determinants had the highest informative value in the models: LV EF <40% (3 points, i.e. 25% of the total score), anterior localization of Q-wave MI (3 points), and Killip class III (3 points).
The obtained total score was used as the basis for the composition of three risk groups of patients with ACS for the prognostication of LV systolic dysfunction after one year.Low risk was determined when the total score was 3 points or less, medium risk -when the total score was 4-5 points, and high risk -when the total score was 6-12 points.More than one-half of patients (58.2%) during the acute period were assigned to the low risk group, one-tenth (13.9%) of patients -to the medium risk group, and nearly one-third of patients (27.9%) -to the highrisk group for LV systolic dysfunction (Fig. 2).
LV systolic dysfunction, prognosticated during the acute period of ACS, after one year was determined in the majority of patients in the high-risk group, in onethird of patients in the medium risk group, and in less than one-fifth of patients in the low risk group (P<0.000).

Table 3. The models of the determinants of acute coronary syndromes for the prognostication of LV systolic dysfunction after one year
Determinants during the acute period p I LV ejection fraction <40%

Prognostication of late left ventricular systolic dysfunction
The comparison of the incidence of LV systolic dysfunction after one year in different risk groups of patients of the studied group with the incidence of LV systolic dysfunction after one year in the examined group did not yield any statistically significant difference (in the high risk group -84.3 and 78.6%; in the medium risk group -39.3 and 50.0%; and in the low risk group -17.4 and 15.0%, P>0.05) (Fig. 3).

Discussion
Most frequently LV systolic dysfunction is caused by ACS.The rate of the progression of LV systolic dysfunction and its clinical manifestation -heart failure -is determined by the degree and duration of myocardial ischemia, stunning myocardium, the damaged area of the myocardium, the localization of the damage, the degree of infarct-related coronary artery lesion, and changes in the myocardium prior to ACS (8)(9)(10)(11).In the presence of myocardial changes, the course of LV systolic dysfunction is related to the myocardial remodeling process and its consequences, dilatation of cardiac chambers, mitral regurgitation, and diastolic dysfunction.LV systolic dysfunction is significantly influenced by changes in the myocardium (hypertensive or diabetic cardiomyopathy) caused by risk factors -arterial hypertension and diabetes mellitus -before ACS.Increased activity of neurohumoral factors (renin-angiotensin system, genome expression, and cell mediatorsendothelin and growth factor), as well as age, gender, and lifestyle are equally important for the development

Low
Moderate High of LV systolic dysfunction and its sequelae (12,13).
It is obvious that the prognostication of the clinical course of LV systolic dysfunction, related to the aforementioned factors (some precipitating and some suppressing its progression), is complicated, as is the relationship of LV systolic dysfunction with heart failure.Martinez-Salles et al. indicate that LV systolic dysfunction following previous MI is a significant prognostic factor for the evaluation of heart failure and mortality (14).However, in patients with ACS in whom LV systolic dysfunction was detected during the acute period, the prognosis and the relationship of the condition with the development of heart failure (HF) cannot be determined based solely on the decreased LV EF.LV systolic dysfunction may develop within the first hours or within the first several days from the occurrence of ACS, may pass or persist, may be asymptomatic, and may manifest itself through acute HF or -later on -through chronic HF (15,16).It has been indicated that systolic dysfunction (LV EF <40%) is detected in 40% of patients with MI and later on in 1.3-8.6%cases per year (17)(18)(19)(20).
Although LV systolic dysfunction resulting in HF is a common complication of ACS, data on the prognostication of its later course are scarce.Most scientific publications focus on LV remodeling and HF at the same time evaluating LV systolic dysfunction.
LV systolic dysfunction during the acute period of the first ACS was detected in less than one-third (30.3%) of our studied patients.The lower incidence of LV systolic dysfunction, compared to that indicated by other authors, may be due to the difference in the studied contingents -our patients had unstable angina pectoris (UAP) and MI for the first time and survived for one year without any recurrence of ACS.
We found that the risk of the persistence and development of LV systolic dysfunction following ACS was not uniform.LV systolic dysfunction that developed during the acute period of ACS persisted after one year in the majority of the studied patients (65.3%) and returned to normal in one-third of patients (34.7%), whereas 19.1% of patients with previously normal LV systolic function developed LV systolic dysfunction; thus, the incidence of LV systolic dysfunction increased by 3.2%.The instability of LV systolic dysfunction that develops during the acute period of ACS is another reason for the prognostication of LV systolic dysfunction that may develop later on.
The recovery in LV EF after one year in one-third of patients may have been conditioned by the impairment of LV function during the first days of ACS that occurred as a result of damage to certain segments of the myocardium, whose function subsequently improved after the normalization of blood flow in coronary arteries.In part of patients with remaining large-scale myocardial damage, failed or delayed normalization of blood circulation in the CA resulted in the myocardial function remaining low or decreasing further due to LV remodeling processes.Gaudron and Gianuzi et al. indicated that progressing late LV remodeling that results in LV systolic dysfunction develops in one-fifth of patients who had MI (21,22).According to Zhang et al., late remodeling of the myocardium occurs if MI involves more than 15% of the myocardium in case of anterior MI and more than 20% of the myocardium in case of inferior MI (23).
The most significant independent determinants of the acute period of ACS for the prognostication of late LV systolic dysfunction were used in our designed model: decreased LV systolic function (EF <40%), anterior Qwave MI, Killip class III-IV, frequent ventricular extrasystoles, pseudo-normal/restrictive LV dysfunction, and LV WMI>1.5.The determinants of CA stenoses and mitral regurgitation II-III° that influenced LV systolic dysfunction were strongly correlated with the aforementioned determinants, but their informative value was lower and did not increase the accuracy of the model.The determinants of the acute period of ACS are indicated by numerous researchers as determinants also having a prognostic value for the prognostication of the unfavorable course of the disease (LV remodeling, the development of chronic HF, and death) and used in the development of models for the prognostication of such events (24)(25)(26)(27)(28)(29)(30).
The determinants of the acute period of ACS, reflecting an unfavorable course of the disease, were evaluated in points, and a mathematical model was designed allowing for the prognostication of the risk for late LV systolic dysfunction.Our model for the prognostication of late LV systolic dysfunction during the acute period of ACS is simple and is based on standard -clinical and Echo KG -findings; the scoring system prognosticates individual risk for late LV systolic dysfunction, the model has good sensitivity and specificity, and correct prognosis is made in the majority of cases.The selection of high-risk patients (in whom LV systolic dysfunction may either persist or develop during the later period) during the acute period of ACS may help in planning the treatment and close observation of such patients.This would decrease the risk of chronic HF and death.

Conclusions
1. Left ventricular systolic dysfunction that developed during the first acute coronary syndrome after one year persisted in more than one-half (65.3%) of patients and returned to normal in one-third (34.7%) of patients.
2. In the majority of patients with normal systolic left ventricular function during the acute period of acute coronary syndrome, this function remained normal after one year, while one-fifth (19.1%) of such patients developed left ventricular systolic dysfunction.
3. The determinants of the acute period of acute coronary syndrome, which were included into the mathematical model for the prognostication of late left ventricular systolic dysfunction after one year, were the following: LV EF <40%, anterior localization of Q-wave MI, Killip class III-IV, pseudo-normal or restrictive left ventricular diastolic dysfunction, and frequent ventricular extrasystoles.
4. When applying the designed mathematical model, late left ventricular systolic dysfunction was correctly prognosticated in 84.3% of high-risk patients in the studied group, and in 78.6% of patients in the examined group.

Fig. 1 .
Fig. 1.The incidence of LV systolic dysfunction among patients with first acute coronary syndrome during the acute period and after one year LV -left ventricle; ACS -acute coronary syndrome; EF -ejection fraction.

Fig. 2 .
Fig. 2. The distribution of patients in the studied and the examined groups during the acute period of ACS according to the risk of LV systolic dysfunction after one year LV -left ventricle, ACS -acute coronary syndrome.

Fig. 3 .
Fig. 3.The incidence of LV systolic dysfunction after one year in the studied and the examined groups according to the risk prognosticated during the acute period of ACS LV -left ventricle, ACS -acute coronary syndrome.

Table 1 . Characteristics of the groups
CA -coronary artery, MI -myocardial infarction.*No significant difference was found.