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Oct 30, 2015 - were defined as grade ≥2 by Rentrop classification. .... Heart failure class on presentation was assessed by Killip classifica- tion [7]: I – no ...
International Journal of Cardiology 203 (2016) 667–671

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Predicting ischemic mitral regurgitation in patients with acute ST-elevation myocardial infarction: Does time to reperfusion really matter and what is the role of collateral circulation? Zivile Valuckiene a,⁎, Povilas Budrys b, Renaldas Jurkevicius a a b

Department of Cardiology, Lithuanian University of Health Sciences, Lithuania Faculty of Medicine, Lithuanian University of Health Sciences, Lithuania

a r t i c l e

i n f o

Article history: Received 11 June 2015 Received in revised form 29 October 2015 Accepted 30 October 2015 Available online 30 October 2015 Keywords: Mitral regurgitation Collateral circulation Reperfusion time

a b s t r a c t Background/Objectives: Ischemic mitral regurgitation (MR) is an adverse prognostic factor. We aimed to assess the role of time delay from symptom onset to reperfusion, and the impact of collateral circulation to incidence of MR in relation to established echocardiographic and clinical risk factors. Methods: Patients with STEMI presenting within 12 h from symptom onset and treated with primary percutaneous coronary intervention (PPCI) at Hospital of Lithuanian University of Health Sciences were enrolled. Echocardiography was performed after PPCI. Based on MR grade, patients were divided into no significant MR (NMR, grade 0-I MR, N = 102) and ischemic MR (IMR, grade ≥ 2 MR, N = 71) groups. Well-developed collaterals were defined as grade ≥2 by Rentrop classification. Continuous variables were compared by independent samples Student's T-test. Multivariate logistic regression analysis was used to identify independent predictors of ischemic MR. Results: Time to reperfusion, MI localization, TIMI flow before/after PCI was similar between the groups. IMR group patients were elder, more often females and non-smokers, had lower body mass index, higher prevalence of multi-vessel coronary artery disease (CAD), better-developed collateral supply, greater left ventricular enddiastolic diameter index, left atrial index, pulmonary artery systolic pressure and lower ejection fraction. Multivariate logistic regression analysis revealed that ischemic MR is predicted by female gender, well-developed collateral supply, presence of multi-vessel CAD, and lower EF. Conclusion: In acute STEMI significant MR is unrelated to ischemic time and is predicted by female gender, lower EF, multi-vessel CAD and well-developed collateral supply to the infarct region. © 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction Early reperfusion strategy in ST-elevation myocardial infarction (MI) improves patient outcomes. Time to reperfusion has major impact on extent of myocardial necrosis, preservation of left ventricular (LV) function and in preventing LV remodeling [1]. The grade of ischemic mitral regurgitation (MR) has been shown to correlate to myocardial viability: the presence of viable myocardium in MI zone reduces LV remodeling and prevents from development or worsening of MR [2]. However, moderate or severe MR detected early by echocardiography is independently associated with worse long-term prognosis in ST-elevation MI (STEMI) patients treated with primary percutaneous coronary intervention (PCI) [3].

⁎ Corresponding author at: Department of Cardiology, Lithuanian University of Health Sciences, Eivenių 2, 50009 Kaunas, Lithuania. E-mail address: [email protected] (Z. Valuckiene).

Ischemic MR is known to be dynamic in nature: only a proportion of patients develop MR after an ischemic event, and MR may change in grade on long-term follow-up. Prognostic implications are clinically relevant while following up post-ST-elevation MI (STEMI) patients and planning treatment interventions [3,4]. The aim of this study was to assess the impact of time from symptom onset to reperfusion therapy and presence of collateral circulation to the infarct zone to incidence of MR in acute STEMI patients, and relate these factors to established echocardiographic and clinical risk criteria. 2. Methods Patients who presented with first ever ST-elevation MI and were treated with primary percutaneous coronary intervention (PCI) at Hospital of Lithuanian University of Health Sciences Kaunas Clinics between December 2013 and September 2014 were enrolled into the study. Inclusion criteria were first ever manifestation of acute coronary syndrome, ST-segment elevation on ECG, presentation within 12 h

http://dx.doi.org/10.1016/j.ijcard.2015.10.225 0167-5273/© 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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from onset of symptoms. Patients were excluded from enrollment in the presence of any of the following: previous history of ischemic heart disease (IHD) (known coronary artery disease, previous MI, PCI, coronary artery bypass surgery), suboptimal echocardiographic imaging quality, structural heart valve pathology (including previous valvular surgery), more than mild aortic valve insufficiency, previously known MR. Two hundred twenty patients met the inclusion criteria. Due to exclusion criteria the final study population consisted of 173 patients. STEMI diagnosis was confirmed based on patient's history, electrocardiographic (ECG) findings (more than 1 mm ST-segment elevation on two concordant ECG leads, new left bundle branch block), identifiable culprit lesion on coronary angiogram and elevated cardio specific serum markers (troponin I) [5]. Location of MI was defined as anterior (ST-segment elevation in ECG leads V1–V6, culprit lesion in left anterior descending coronary artery) or inferior/posterior (ST-segment elevation in ECG leads II, III, aVF, and culprit lesion in right coronary or left circumflex coronary arteries). All patients were treated according to ESC Guidelines on Myocardial Revascularization [6]: 5000 units of unfractionated Heparin were administered intravenously, followed by an oral loading dose of 300 mg of Aspirin and 600 mg of Clopidogrel upon first medical contact. No other antiplatelet or fibrinolytic treatment was administered before coronary angiography. All patients were subsequently treated with primary percutaneous coronary intervention. Betablocker, angiotensin-converting enzyme inhibitor and statin were administered after reperfusion therapy based on clinical judgement and ESC recommendations. The cardiovascular risk factors were recorded using a standard questionnaire. Arterial hypertension was defined as presence of increased blood pressure (BP) N 140/90 mmHg on serial measurements during in-hospital stay or current use of anti-hypertensive medication. Diabetes mellitus was confirmed based on established medical history or by detecting elevated fasting plasma glucose ≥ 7.0 mmol/l on serial in-hospital measurements. Dyslipidemia was defined as elevated total (N 5.2 mmol/L) or low-density lipoprotein (LDL) level (N2.59 mmol/L), or low levels of high-density lipoprotein (HDL) cholesterol (b 1.55 mmol/L). Patient was considered as a smoker if he was currently smoking or was a smoker in the past. Heart failure class on presentation was assessed by Killip classification [7]: I – no clinical signs of heart failure, II – rales or crackles in the lungs, gallop rhythm, elevated jugular venous pressure, III – frank pulmonary edema, IV – cardiogenic shock or hypotension, evidence of peripheral vasoconstriction. Time from symptom onset was obtained from the patient during the first medical contact and documented in the medical health records. Time of balloon inflation was recorded during the primary PCI procedure. This study complies with the Declaration of Helsinki, and the locally appointed ethics committee has approved the research protocol. Informed consent has been obtained from the subjects to use the medical data for research purposes.

antegrade flow filling the distal segments; TIMI 3 – normal coronary flow [8]. Rentrop classification was used to grade collateral flow to the culprit artery: 0 – none; 1 – filling of side branches of the distal artery via collateral channels without visualization of the epicardial segment; 2 – partial filling of the epicardial segment via collateral channels; 3 – complete filling of the epicardial segment of the artery via collateral channels [9]. The patient was considered to have well-developed collaterals if the collaterals to the distal coronary bed were grade ≥ 2 (Rentrop). Chronic total occlusion (CTO) of a non-infarct-related artery was ascertained if a complete collateralized blockage with no antegrade flow (TIMI 0) of a non-infarct-related artery was found on coronary angiography which met angiographic and clinical criteria for duration of N 3 months with identifiable other STEMI-related culprit lesion.

3. Coronary angiography

Continuous variables were expressed as mean ± 1 standard deviation and compared with independent samples T-test. Categorical variables were expressed as frequencies and compared with χ2 test. A multivariate logistic regression analysis was used to identify the independent predictors of ischemic MR development for these parameters: age, gender, body mass index, LV EDDi, LAi, EF, collateral development (Rentrop grade 2–3), presence of multi-vessel coronary artery disease (CAD). The final risk stratification model was based on selected variables, which were significant at p ≤ 0.05 level for predicting ischemic MR, following multivariate regression analysis (gender, ejection fraction, collateral supply of Rentrop class ≥2, presence of multi-vessel coronary artery disease) and age. The accuracy of the model predicting ischemic MR was assessed by the receiver operating characteristic (ROC) curve.

One experienced interventional cardiologist evaluated coronary angiography data of all study participants. Angiographically significant lesion was defined as a luminal narrowing of ≥50% in a major epicardial vessel with diameter ≥2.5 mm. Culprit lesion was determined based on angiographic appearance (acute blockage or significant luminal compromise resulting in limitation of antegrade coronary blood flow) and ECG data (supplied territory corresponding to ST-elevation region on ECG). Thrombolysis in Myocardial Infarction (TIMI) flow grading system was used to evaluate myocardial perfusion in the infarctrelated artery before and after PCI: TIMI 0 – absence of any antegrade flow beyond the occlusion; TIMI 1 – antegrade contrast penetration beyond the occlusion, with incomplete distal filling; TIMI 2 – slow

4. Echocardiography Echocardiography was performed within 72 h from admission and primary PCI. Mitral regurgitation was assessed according to the ESC/EACVI guidelines by proximal isovelocity surface area (PISA) method or semi quantitative color flow Doppler when quantitative assessment of MR was not feasible (unmeasurable PISA, or continuous Doppler trace) [10]. According to the degree of MR patients were divided into 2 groups: patients with no significant MR (NMR group, grade 0-I MR, N = 102) and patients with ischemic MR (IMR group, grade ≥2 MR, N = 71). Left ventricular end-diastolic diameter (LV EDD) was measured in parasternal long axis view, at end diastole, on the frame where LV cavity was largest. LV EDD index (LV EDDi) was calculated by dividing LV EDD (mm) by body surface area (m2). Myocardial mass (MM) was calculated by Devereux formula [11]. Myocardial mass index (MMI) was calculated by dividing MM (g) by body surface area (m2). LV ejection fraction (EF) was calculated by standard Simpson's biplane method [12]. Wall motion score was evaluated in a 16-segment model: each segment was assessed in multiple views [13]. Systolic myocardial motion and thickening was graded as 1 – normokinesis or hyperkinesis, 2 – hypokinesis, 3 – akinesis, 4 – dyskinesis, 5 – aneurysm. Total wall motion score was indexed to the total number of segments analysed [16] to derive the wall motion score index (WMSI). Right ventricular (RV) diameter was measured in apical 4 chamber view, at the mid-ventricular level of RV, at end diastole. Left atrial (LA) diameter was estimated at end-systole in parasternal long axis, perpendicularly to the LA walls from leading edge of the posterior aortic wall to the leading edge of the posterior LA wall. LA diameter index (LAi) was obtained by indexing the measured value to individual BSA. Pulmonary artery systolic pressure (PASP) was estimated by modified Bernoulli equation from tricuspid valve regurgitation velocity [14]. Estimated right atrial pressure was added according to respiratory variability of inferior vena cava.

5. Statistical analysis

Z. Valuckiene et al. / International Journal of Cardiology 203 (2016) 667–671 Table 1 Demographic and clinical profile of 173 patients with first ever ST-segment elevation myocardial infarction. Variable Demographics Age (years) Gender (male/%) Risk factor profile, comorbidities Body mass index (kg/m2) Hypertension, n (%) Dyslipidemia, n (%) Diabetes, n (%) Smoking, n (%) Symptom onset to balloon time Immediate presenters (0–3 h), n (%) Early presenters (3–6 h), n (%) Late presenters (6–12 h), n (%) MI localization, n (%) Anterior Inferior/Posterior

NMR group (n = 102)

IMR group (n = 71)

P

62 ± 12.2 85/83.3

69 ± 12.4 40/56.3

b0.001 b0.001

29.2 ± 5.2 84 (82.4) 91 (89.2) 13 (12.7) 48 (48.5) 4.5 ± 3.0 43 (42.2) 27 (26.5) 32 (31.4)

27.5 ± 4.4 58 (81.7) 58 (84.1) 7 (9.9) 14 (21.2) 5.0 ± 3.5 27 (38.0) 25 (35.2) 19 (26.8)

0.027 0.91 0.33 0.56 b0.001 0.38

60 (58.8) 42 (41.2)

33 (46.5) 38 (53.5)

0.1

0.46

MR — mitral regurgitation, NMR — no MR group, IMR — ischemic MR group, MI — myocardial infarction. Data is presented as mean ± standard deviation and number (percentage).

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There was no difference in coronary dominance, culprit artery, TIMI flow before or after PCI between the groups (Table 2). IMR group patients had higher prevalence of multi-vessel CAD and betterdeveloped collateral supply to the infarct region. CTO lesions in nonculprit arteries were more prevalent in IMR group compared to NMR group, however statistical significance of this finding was borderline (p = 0.05). Patients in IMR group had significantly greater LV EDDi, MMI, LAi, PASP and lower EF (Table 3). WMSI was higher in IMR group. There was no significant difference in MMI, and RV diameters between the groups. There were significantly more patients presenting in Killip heart failure class III–IV and higher incidence of in-hospital deaths in IMR group compared to NMR group (Table 4). In-hospital treatment duration was also longer in IMR group. Multivariate logistic regression analysis has shown that in acute STEMI patients ischemic MR is predicted by female gender, welldeveloped collateral supply to ischemic territory, presence of multivessel CAD, and lower EF (Table 5). A model predicting ischemic MR (including age, gender, ejection fraction, collateral supply of Rentrop class ≥2 and presence of multi-vessel coronary artery disease) yielded an area under the ROC curve of 0.84, p b 0.001 (Fig. 1).

6. Results

7. Discussion

Patients in IMR group were elder, had lower BMI, were more likely to be females and non-smokers (Table 1). There was no difference in prevalence of arterial hypertension, dyslipidemia and diabetes mellitus between the groups. Time from symptom onset to reperfusion and distribution of MI localization was also similar.

Presence of ischemic MR carries an established adverse prognosis in acute STEMI patients. Patients at risk are elder, more likely to be female, to have lower EF and multi-vessel CAD — these findings are well acknowledged in previous reports [3,4,15]. LA size is a reliable indicator of LV diastolic function and represents long-standing diastolic LV filling status instead of acute variations reflected by echocardiographic Doppler parameters [16,17]. Higher proportion of elderly patients with underlying ‘silent’ ischemic heart disease in IMR group quite naturally manifests higher degree of diastolic dysfunction indicated by increased LA index. On the other hand, LA enlargement is common in chronic volume overload and correlates to both – severity and duration – of MR [18]; consequently, all possible care during recruitment and echocardiographic analysis has been taken to exclude possible cases of previously underlying MR. Time to reperfusion is an important factor in salvaging the myocardium at risk. Early reperfusion improves immediate and long-term outcomes in patients who present with STEMI [8,19]. However, ischemic time appears to not be directly related to ischemic MR manifestation in acute STEMI patients treated with primary PCI as has been shown in our study. Although recent reports emphasize the importance of collateral supply in reduction of ischemic MR [20], a considerable proportion of our study participants exhibited ischemic MR despite well-developed collateral circulation to occluded culprit artery territory.

Table 2 Angiographic data of 173 patients with first ever ST-segment elevation myocardial infarction. Data Coronary dominance, n (%) Right Left Balanced Culprit artery, n (%) Left anterior descending Left circumflex Right No. of affected coronary arteries, n (%) 1 2 3 Left main disease TIMI flow pre-PCI, n (%) 0 1 2 3 TIMI flow post-PCI, n (%) 0 1 2 3 Collaterals to MI area (Rentrop), n (%) 0 1 2 3 Presence of chronic total occlusion, n (%)

NMR group (n = 102)

IMR group (n = 71)

P

79 (77.5) 16 (15.7) 7 (6.9)

58 (84.1) 6 (8.7) 5 (7.2)

0.41

58 (56.9) 9 (8.8) 35 (34.3)

32 (45.1) 8 (11.3) 31 (43.7)

0.31

38 (37.3)a 33 (32.4)a 23 (22.5)a 8 (7.8)a

15 (21.1)b 21 (29.6)a 31 (43.7)b 4 (5.6)a

61 (59.8) 7 (6.9) 25 (24.5) 9 (8.8)

51 (71.8) 3 (4.2) 13 (18.3) 4 (5.6)

0.44

0 0 17 (16.7) 85 (83.3)

1 (1.4) 1 (1.4) 11 (15.5) 58 (81.7)

0.4

74 (72.5)a 11 (10.8)a 14 (13.7)a 3 (2.9)a 5 (4.9)

30 (44.1)b 11 (16.2)a 19 (27.9)b 8 (11.8)b 9 (13.2)

0.02

Table 3 Echocardiographic parameters of 173 patients with first ever ST-segment elevation myocardial infarction. Parameter

0.01 0.05

MR — mitral regurgitation, NMR —no MR group, IMR — ischemic MR group, TIMI flow: thrombolysis in myocardial infarction flow grade, MI — myocardial infarction, PCI: percutaneous coronary intervention. Data is presented as number (percentage). a, b — Difference is statistically significant between different letters (a, b) and insignificant between the same letters.

LVEDD, mm LVEDD index, mm/m2 MMI, g/m2 EF, % WMSI LA diameter, mm LA index, mm/m2 RV diameter, mm PASP, mmHg

NMR group (n = 102)

IMR group (n = 71)

P

48.3 ± 5.5 23.7 ± 2.8 100.5 ± 22.1 43.1 ± 8.7 1.6 ± 0.4 40.2 ± 4.4 19.8 ± 2.2 31.4 ± 5.2 33.1 ± 6.8

48.8 ± 5.8 25.7 ± 3.2 110.2 ± 31.4 38.6 ± 10.4 1.8 ± 0.4 40.6 ± 4.6 21.6 ± 2.5 31.8 ± 5.0 39.6 ± 11.2

0.56 b0.001 0.02 0.02 0.04 0.58 b0.001 0.61 b0.001

MR — mitral regurgitation, NMR — no MR group, IMR — ischemic MR group, LVEDD: left ventricular end-diastolic diameter, MMI: myocardial mass index, EF: ejection fraction, WMSI: wall motion score index, LA: left atrium, RV: right ventricle, PASP: pulmonary artery systolic pressure. Data is presented as mean ± standard deviation.

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Table 4 In-hospital outcomes and distribution of heart failure (Killip) classes in study groups. Variable Killip HF class, n (%) I–II III–IV In-hospital outcomes In-hospital treatment duration, days In-hospital death, n (%)

NMR (n = 102)

IMR group (n = 71)

P

94 (92.2)a 8 (7.8)a

58 (81.7)b 13 (18.3)b

0.04

8.1 ± 2.1 1 (1)

9.1 ± 3.0 5 (7)

0.02 0.03

MR — mitral regurgitation, NMR — no MR group, IMR — ischemic MR group. In-hospital treatment duration is presented as mean ± standard deviation, other data — as number (percentage). a, b — Difference is statistically significant between different letters (a, b) and insignificant between the same letters.

Collateral circulation is known to maintain myocardial viability, and plays protective role in limiting the infarct size and in maintaining hemodynamic stability in acute ischemic events [21,22]. Animal models have demonstrated that significant increase in collateral blood flow within the infarct area is present during the first hour after coronary artery occlusion, and further increase is observed upon follow-up [23]. However, human observational studies show that there is no increase in the prevalence of angiographically visible collateral flow with increasing time to baseline angiography in acute MI patients. These findings suggest that all collateral channels identifiable on baseline angiography most likely had developed due to preceding high-grade coronary artery stenosis [24]. Higher prevalence of multi-vessel CAD and collateral development are also in keeping with the hypothesis of prior ‘silent’ and unrecognized ischemic heart disease with an underlying degree of LV remodeling suggested by larger LV EDDi. In this study, we tested the hypothesis whether patients with welldeveloped collateral circulation to the infarct area have less incidence of MR due to better-preserved myocardial viability upon presentation with acute STEMI. The observed effect of collateral circulation to the incidence of MR was quite the opposite from expected: well-developed collaterals to the infarct region upon presentation do not reduce MR incidence, but are a significant independent predictor of functional MR in STEMI patients. Preventive role of collateral blood supply regarding ischemic MR is far negatively outweighed by underlying LV remodeling as the result of preceding IHD. Prior studies have demonstrated that although gradual development of collaterals can prevent from acute ischemic event in the presence of increasing coronary artery obstruction, collateral flow reserve is rarely sufficient to provide adequate myocardial perfusion even in stable CAD patients with chronically occluded coronary arteries [25–27]. The role of collateral circulation is even less pronounced in preventing acute ischemia upon abrupt obstruction of the coronary vessel in acute ischemic event [28,29]. Which is more, experimental studies have demonstrated that there is a transmural difference in the effectiveness of collateral supply: collateral flow is significantly greater in the epicardial than endo- or midventricular layers, irrespectively of site [30]. However, further studies Table 5 Odds ratios for grade ≥2 ischemic MR in multivariate logistic regression analysis. Predictor Age Female gender Body mass index Collaterals Rentrop class ≥2 Multi-vessel CAD LV EDDi LA index EF

OR (95% CI)

P

1.0 (0.9–1.1) 3.5 (1.4–9.2) 0.9 (0.9–1.0) 2.9 (1.2–7.2) 3.9 (1.4–11.1) 1.1 (1.0–1.3) 1.2 (1.0–1.5) 0.9 (0.9–1.0)

0.13 0.01 0.26 0.02 0.02 0.13 0.09 0.01

MR — mitral regurgitation, OR — odds ratio, CI — confidence interval, CAD — coronary artery disease, LV EDDi — left ventricular end-diastolic diameter index, LA — left atrium, EF — ejection fraction.

Fig. 1. Discriminative power of the prognostic model using age, gender, ejection fraction, collateral supply and presence of multi-vessel coronary artery disease for the risk stratification of ischemic mitral regurgitation in patients with first acute ST-elevation myocardial infarction. Sensitivity 70.1%. Specificity 84.5%. Positive predictive value 75.8%. Negative predictive value 80.4%, p b 0.001.

are needed to assess the impact of collateral flow on ischemic MR on long-term follow-up. All patients in our study were treated with primary PCI for culprit lesion only. Conventional management strategies for treating STEMI patients with multi-vessel CAD may vary from complete interventional revascularization including non-culprit lesions during index procedure to medical therapy, staged PCI or subsequent surgical revascularization [31–33]. Impact of completeness of revascularization and residual ischemic myocardial burden on ischemic MR is a potential direction for future investigations.

8. Study limitations As left ventricular function and degree of ischemic MR may change on long-term follow-up after myocardial reperfusion therapy, lack of follow-up of these patients in assessing the impact of collateral flow on prevalence of ischemic MR is among the limitations of this study. Presence of MR in some patients may not be related to the acute ischemic event despite multiple exclusion criteria to rule out such cases. Collateral supply may have been underestimated due to competitive flow physiology in patients with preserved antegrade flow. The population presented in the study belongs to a single centre.

9. Conclusion In acute first-presentation STEMI population presence of significant MR is unrelated to ischemic time and associated with female gender, lower EF, presence of multi-vessel CAD and well-developed collateral supply to the MI region.

Conflict of interest Authors declare no conflict of interest.

Z. Valuckiene et al. / International Journal of Cardiology 203 (2016) 667–671

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