IMR, Ischemic mitral regurgitation;
MI, myocardial infarction;
ACS, acute coronary syndrome;
PCI, percutaneous coronary intervention;
LV, Left Ventricle;
PISA, Proximal Isovelocity Surface Area;
EOA, effective orifice area;
RV, regurgitation volume;
RF, regurgitation fraction;
SWMI, segmental wall motion index;
CABG, coronary artery bypass graft;
NYHA, New York Heart Association;
SD, standard deviation;
EF, Ejection Fraction;
RJA, regurge jet area;
LVEDV, Left Ventricular End-Diastolic Volume;
LVESV, Left Ventricular End-Systolic Volume;
STEMI, ST Elevation Myocardial Infarction;
NSTEMI, Non ST elevation myocardial infarction
Ischemic mitral regurgitation (IMR) predominantly occurs due to a valvular dysfunction without any intrinsic abnormalities of the mitral valve apparatus in the setting of coronary heart disease. It is a frequent complication of acute coronary syndrome (ACS) and has several etiologies. It may result from altered ventricular geometry, papillary muscle dysfunction, incomplete mitral leaflet coaptation, and regional wall motion abnormalities [1,2].
The existence and severity of IMR is associated with an adverse prognosis. Moderate and severe IMR has been associated with lower long-term survival in patients after an acute myocardial infarction (MI).  Moreover, worsening of IMR during the first month after acute MI was associated with an increased risk of adverse outcomes, and patients whose IMR progressed over the 20-month follow-up period had increased hospitalization for heart failure during those periods. [3–6]
Although early percutaneous coronary intervention (PCI) for ACS is known to improve outcome, IMR after MI worsens the outcome. However, the effect of early PCI on IMR incidence has not been specifically studied. [7,8]
This study was designed to measure the impact of early PCI on an existing IMR in patients with first attack of ACS by comparing the change of the severity of IMR in patients treated with and without total revascularization by PCI.
2. Patients and methods
The study was conducted as an open-label, multicenter, prospective, observational trial between July 2015 and February 2017 in the Critical care department at Cairo University, Egypt, and the Cardiology department at Al Azher University, Egypt.
Inclusion Criteria: Patients presenting with acute coronary syndrome for the first time without clinical heart failure symptoms (Killip class I) .
The study protocol was approved by the local Ethics. Informed consent was obtained from all patients participating in the study. This study did not interfere with the normal routine patient management.
Exclusion Criteria: (1) Previous MI; (2) history of PCI or coronary artery bypass graft; (3) non-ischemic cause of mitral regurge documented by history, previous ECG and previous and baseline echocardiography; (4) dilated cardiomyopathy or congenital heart disease; (5) ACS after revascularization or restenosis; (6) atrial fibrillation; (7) inadequate echocardiographic images; (8) no longer receiving follow up care.
2.2. Evaluation of patients
All included patients were subjected to the following:
2.2.1. Clinical and sociodemographic evaluation
Information including age, gender and current smoker/non-smoker. Hypertension was defined (based on criteria of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) as a systolic blood pressure ≥ 140 mmHg or a diastolic blood pressure ≥ 90mmhg within 24 h of admission.  Dyslipidemia was considered to be present when the total cholesterol was >200 mg per deciliter or if triglycerides were >150 mg per deciliter within 24 h of admission.
2.2.2. Echocardiographic evaluation
All patients that were enrolled in and completed the study underwent transthoracic color Doppler echocardiography on the admission day and after six months. The echocardiography images were obtained using a transducer 2.5–3.5 MHz with 2D guided M-mode facilities. All patients were examined in the partial left lateral decubitus and were angled according to necessity to obtain optimal windows for optimal views, according to the recommendations of the American Society of Echocardiography . Images were obtained in the parasternal long axis, parasternal short axis (mid-level), and apical two and four chamber views. Optimization was performed using harmonic imaging, gain, dynamic range, frequency, sector width, and focus to improve signal-to-noise ratio and provide optimal endocardial definition. Images were accepted for analysis according to the guidelines proposed by Gordon et al. (1983), when at least 80% of endocardium was noted.  LV end diastolic and systolic volumes and ejection fraction were assessed by apical four chamber and two chamber views with the modified Simpson's method . This was performed at both end-diastole and systole. End-diastole was taken to coincide with the Q-wave on the electrocardiogram, and end-systole was selected by identifying the frame with smallest LV cavity cross-sectional area in both apical views prior to mitral valve opening. The parameters were averaged from three consecutive measurements. According to the guidelines of the American College of Cardiology/American Heart Association (ACC/AHA) , mitral regurgitation was evaluated; 1) semiquantitatively by color flow mapping for estimation of the regurgitant jet extension in the left atrium and the vena contracta width which is the smallest, highest velocity region of a flow jet and is typically located at or just downstream from the regurgitation orifice (Tables 1 and 2) quantitatively using the proximal isovelocity surface area (PISA) method in order to determine quantitative MR parameters such as effective orifice area (EOA), regurgitation volume (RV), and regurgitation fraction (RF). Segmental wall motion index (SWMI), a semi-quantitative analysis of the regional systolic function, was assessed. Each segment of the 16-segments of the LV was analyzed individually and scored on the basis of its motion and systolic thickening. The index is derived by dividing the total of the wall motion scores of each segment by 16. 
2.2.3. Coronary angiography and PCI
All patients underwent coronary angiography according to standard techniques. Stenotic lesions were graded subjectively by visual consensus of at least 2 experienced observers. The extent of coronary artery disease was characterized by the traditional 1-, 2-, or 3-vessel disease classification. According to the result, the patients divided into two groups: group A; those who had undergone successful total revascularization of a significant coronary artery disease (≥70% lesion in one or more coronary vessels) using PCI, and group B; those who had optimal medical treatment with no total revascularization, failed PCI or for CABG. Group A patients subdivided into two subgroups according to the short-term improvement in the severity of IMR after PCI; that is, subgroup I, patients with improvement of the IMR; and subgroup II, patients with no improvement of IMR.
2.2.4. Functional evaluation
Functional capacities of the patients were assessed according to the New York Heart Association (NYHA) classification at the beginning and at the sixth month. 
2.2.5. The statistics
Data were statistically described in terms of range, mean ± standard deviation (± SD), frequencies (number of cases), and relative frequencies (percentages) when appropriate. Comparison of quantitative variables between the study groups was done using independent t test and paired t test was used to compare data on admission with those 6 months later. In order to compare the categorical data, a Chi square (χ2) test was performed. An exact test was used when the expected frequency was <5. A probability value (p value) of <0.05 was considered statistically significant. Multivariate logistic regression was used to examine the effect of PCI and the individual risk factors on IMR. All statistical calculations were done using SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) version 21 for Microsoft Windows.
3.1. Demographic data
During the study period, out of 420 patients screened, 271 (65%) patients showed IMR. Only 175 patients underwent successful total revascularization, 149 (85%) of them attended and completed the follow-up examination (group A). Another 96 patients who didn't underwent successful total revascularization were also included and 91 (95%) of them attended and completed the follow-up examination (group B). Out of the 149 patients who underwent successful total revascularization, one hundred and one (68%) showed IMR improvement (subgroup I) and 48 (32%) patients showed no improvement (subgroup II). Figs. 1, 2
There was no significant difference in relation to the baseline features distinguishing the groups A and B and the two subgroups I and II, which include age, gender, current smoking, hypertension, dyslipidemia, diabetes mellitus, and NYHA class. In addition, there was no difference between the two subgroups in terms of the clinical diagnosis and location of MI. Also, there were no significant differences between the two subgroups in relation to the baseline echocardiographic and coronary angiography results (Tables 2–4).
Functional capacities of the patients assessed by NYHA and echocardiographic assessment at 6 months following successful total revascularization revealed a statistically significant improvement in relation to the NYHA, EF, SWMI, RJA, EOA, RV, and RF in group A and subgroup I. On the other hand, there were no significant changes in group B as well as subgroup II (Tables 2, 4).
Following total revascularization by PCI, the mean MR jet area decreased from 4.54 ± 2.21 to 3.46 ± 2.01 cm2 with p < 0.001 in group A. This improvement was statistically significant in all degrees of MR. (Table 5). On the other hand, the mean MR- RJA showed no significant changes after 6 months in group B patients (4.86 ± 1.83 vs 4.81 ± 1.71 cm2 with p = 0.861 and these changes were non-significant in all degrees of MR (Tables 5 and 6).
3.2. Correlative analysis
PCI, EF and SWMI were significant predictors of IMR improvement, as indicated by the highest Exp. to odds ratio (Table 7).
Ischemic mitral regurgitation especially the severe degree is a serious complication of coronary artery disease. Its presence is associated with the development of hemodynamic deterioration, heart failure, and poor outcome . The restoration of coronary blood flow will reduce LV remodeling and will improve regional and global LV function. This strategy is expected to attenuate IMR, which increased our interest in studying the impact of total revascularization by PCI on the incidence of IMR in patients with first attack of ACS .
Ischemic mitral regurgitation was reported to be present in 65% of the screened patients, as determined by echocardiographic examination. This finding agrees with several studies, which reported that mitral regurgitation occurred within several days to one week after acute MI, and was present in 9% to 55% of patients, as determined by auscultation, and in 20% to 56% of patients through echocardiographic examination. Angiographic studies detected IMR in 13% to 19% of patients within 7 h of admission with acute MI. [1,18–21]
Out of the 149 patients underwent complete total revascularization by PCI, 47 (31%) patients showed improvement in the degree of IMR, 91 (61%) showed no change in the degree of IMR, and only 11 (7%) patients showed deterioration of the degree of IMR. Moreover, all the degrees of IMR demonstrated statistically significant improvement of the severity of IMR when assessed by RJA (P < 0.001 for mild degree, 0.049 for moderate degree, and 0.011 for severe degree IMR). In contrast, out of the 91 group B patients, only 10 (11%) patients showed improvement in the degree of IMR and 26 (29%) patients showed deterioration of the degree of IMR. Moreover, all the degrees of IMR demonstrated no statistically significant difference in the severity of IMR when assessed by RJA (P > 0.05).
This study also demonstrated that group A patients especially subgroup I patients showed a statistically significant improvement of the LVEF, SWMI, and NYHA classification, and quantitative MR parameters assessed by echocardiography (EOA, RV, RF) (p < 0.001 for all). A lower LVEF and higher LVEDV and LVESV were associated with subgroup II and did not exhibit any significant improvement during follow up. Enlarged LVEDV and LVESV are thought to indicate ventricular remodeling, where the posterior papillary muscle is displaced, thereby preventing leaflet closure and resulting in no change in IMR during follow up. [22,23]
These findings agree with Waleed et al. , who found that patients with successful reperfusion with PCI showed significant reductions in the severity of IMR. Also, Chue et al.  reported that PCI is highly effective in decreasing the incidence of moderate and severe IMR after acute MI, compared to results with patients with no PCI. Moreover, Trichon et al.  showed that improvement of IMR after revascularization was associated with improved survival compared to patients on medical therapy alone.
IMR results from several anatomical and pathophysiological changes involving the complex interaction between the leaflets, annulus, subvalvular (i.e., papillary muscle) apparatus, and LV wall. The initiating factor is usually LV remodeling converting its shape from ellipsoidal to spherical (increasing the sphericity index), leading to regional annular and subvalvular distortion, and ultimately, poor leaflet coaptation during systole. Moreover, papillary muscle displacement, i.e., tethering, leads to apical tenting of the leaflets (restriction of the motion of the free margins of the leaflets), which impairs good coaptation during systole [3,26]. IMR further inflects the hemodynamic load during the period of active LV remodeling . Ishikawa et al.  reported IMR to be a common cause of congestive heart failure caused by the process of MI remodeling. Early coronary revascularization might be useful in minimizing infarct size and improving LV remodeling .
There were no significant differences between the two group as well as the two subgroups regarding the type of ACS and the angiographic results (number of vessels affected, site, and degree of vessel affection). This observation goes with the results of Maria et al., who observed no clear relationship between the severity of IMR and infarct location. 
In contrast to this study, Chue et al.  demonstrated that PCI remarkably decreased the incidence of moderate or severe IMR in patients with acute STEMI compared to those not receiving PCI. Moreover, Waleed et al.  and Chue et al.  concluded that PCI is more effective in decreasing the incidence of moderate or severe IMR for inferior MI, compared to the results for patients with no PCI.
Also, Pellizzon et al.  demonstrated that IMR was associated with triple-vessel coronary artery disease and a lower incidence of single-vessel coronary artery disease. Moreover, Ho et al.  showed significant improvements in patients with IMR and multivessel disease treated by PCI.
These conflicting data may be related to the higher proportion of those with mild IMR (81 patients “54%”) in this study, while any significant improvements may be more pronounced in those with moderate or severe IMR. Thus, such a finding may support the observation that, in different populations, the predominant mechanism of IMR is complex and may involve either more or less ischemic papillary muscle dysfunction versus valvular dysfunction from LV dilatation and/or dysnychronous myocardial contraction . Many experimental studies have emphasized the importance of the geometry of the LV for normal mitral leaflet coaptation . Remodeling of the ischemic LV, namely its enlargement and assumption of a more spherical shape, leads to an altered axis of papillary muscle contraction, apical tethering of the mitral leaflets, and a restriction of their ability to coapt normally at the annular plane. Additionally, many patients have LV dysfunction, thus decreasing the force available to close the leaflets in the setting of disordered architecture of the mitral apparatus . These several underlying processes are often difficult to separate in a given patient .
Follow up LVEF and SWMI were significant predictors of IMR improvement following PCI. This may support the above observation that IMR improvement is secondary to the improvement of regional and global LV function and attenuation of the LV remodeling, as long as vessel patency is maintained [29,32].
4.1. Limitations and recommendations
(1) the number of included patients was relatively small. Valuable conclusions could be achieved by using a larger study population and a longer follow up, and (2) MR was an operator assessed in this study, and hence interpretation bias cannot be excluded. Other studies including angiographic grading of IMR may be indicated.
Successful total revascularization using early PCI significantly improve IMR parameters.
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