Systolic Function Recovery After ST-Segment Elevation
Myocardial Infarction
D1X XRachid Abou,
D2X XMD,
D3X XMelissa Leung,
D4X XMBBS MBiostat, PhD,
D5X XLaurien Goedemans,
D6X XMD,
D7X XGeorgette E. Hoogslag,
D8X XMD, PhD,
D9X XMartin J. Schalij,
D10X XMD, PhD,
D11X XNina Ajmone Marsan,
D12X XMD, PhD,
D13X XJeroen J. Bax,
D14X XMD, PhD, and
D15X XVictoria Delgado,
D16X XMD, PhD
*
Little is known about the proportion of ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention, who have reduced left ventricular ejection fraction (LVEF) within 48 hours (baseline) of admission and exhibit LVEF recovery under optimal guideline-based medical treatment. Therefore, the present study evaluates the evolution of LVEF in patients after STEMI and under guideline-based medical therapy. In 2,853 STEMI patients treated with primary percuta-neous coronary intervention, echocardiography was performed at baseline and at 6 months follow-up. Patients with previous myocardial infarction, reinfarction, coronary artery bypass grafting or incomplete echocardiographic data at 6 months follow-up were excluded. Reduced LVEF at baseline was defined as<40%. LVEF recovery was defined as LVEF>50% at 6 months follow-up. The prevalence of LVEF <40% at baseline was 13% (n = 371 patients; mean age 60 [range 33 to 88] years; 76% men). At follow-up, 31% of patients remained with a LVEF<40%, 30% showed a LVEF between 41% and 49% and in 39% of patients LVEF improved to>50%. There were no differences in usage of guideline-based medications at discharge across groups. On multivariable analysis, peak troponin T levels (odds ratio [OR] 0.895; p< 0.001), baseline LVEF (OR 1.069; p = 0.023) and absence of significant mitral regurgitation (OR 0.376; p = 0.018) were independently associated with LV recovery at follow-up. In conclusion, the prevalence of LVEF<40% is low. With optimal medical therapy, LVEF normalizes in 39% of patients. Smaller enzy-matic infarct size, baseline LVEF and absence of mitral regurgitation were independently associated with LVEF recovery at follow-up. © 2018 The Author(s). Published by Elsev-ier Inc. This is an open access article under the CC BY-NC-ND license. (http:// creativecommons.org/licenses/by-nc-nd/4.0/) (Am J Cardiol 2018;122:1591−1597)
The implementation of guideline-based secondary preventive therapy to halt left ventricular (LV) remodel-ing and prevent new coronary events has made an important impact on the evolution of LV systolic func-tion after ST-segment elevafunc-tion myocardial infarcfunc-tion (STEMI).1−3 Nevertheless, a substantial proportion of patients after STEMI still remain with reduced LV sys-tolic function.4 Data on LV systolic functional recovery after STEMI treated with primary percutaneous coronary intervention (PCI) are scarce and systematic echocardio-graphic surveillance of large STEMI populations treated according to prevailing guidelines is infrequent.5,6 Therefore, the present study evaluated (1) the prevalence of severe LV systolic dysfunction after first STEMI and
(2) the effect of contemporary guideline-based therapy on the recovery of LV ejection fraction (EF) at 6 months follow-up in a homogenous cohort of STEMI patients treated with primary PCI.
Methods
Of 2,853 patients with first acute STEMI admitted to the Leiden University Medical Center (The Netherlands) and treated with primary PCI between February 2004 and May 2013, patients with LVEF ≤ 40% on 2-dimensional (2D) echocardiography performed within 48 hours of admission were identified and included in the present analysis.7At dis-charge, patients received guideline-based medical therapy according to contemporary guidelines.8,9Clinical and echo-cardiographic evaluation was repeatedly performed at 6 months, according to the institutional guideline-based pre-hospital, in-hospital and outpatient clinical care track proto-col (MISSION!).7Subsequently, patients were divided in 3 groups according to the LVEF at 6 months of follow-up: LVEF ≤ 40% (nonrecovery), LVEF 41% to 49% (partial recovery) and LVEF ≥ 50% (full recovery) (Figure 1). Patients with previous myocardial infarction, reinfarction within 6 months after discharge, coronary artery bypass grafting and patients with incomplete echocardiographic
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. Manuscript received May 27, 2018; revised manuscript received and accepted July 31, 2018.
Funding: The Department of Cardiology of the Leiden University Medical Center received unrestricted research grants from Biotronik, Medtronic, Bos-ton Scientific Corporation and Edwards Lifesciences. Victoria Delgado received speaker fees from Abbott Vascular.
See page 1596 for disclosure information.
*Corresponding author: Tel: +31 71 526 2020; fax: + 31 71 526 6809. E-mail address:V.delgado@lumc.nl(V. Delgado).
www.ajconline.org 0002-9149/© 2018 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
data were excluded from this analysis. For retrospective analysis of clinically acquired data, the institutional review board waived the need for patient written informed con-sent.
Patient demographics and clinical characteristics were recorded. The culprit lesion was identified on invasive coro-nary angiography and the final Thrombolysis In Myocardial Infarction flow after primary PCI was registered. Multives-sel disease was defined as the presence >1 vessel with luminal narrowing ≥ 50%. Cardiovascular medications at hospital discharge were grouped as: antiplatelet agents, angiotensin converter enzyme inhibitors (ACEi) or angio-tensin receptor blockers II (ARB-II), b-blockers, aldoste-rone antagonists, and statins. Medical treatment was optimized according to contemporary guidelines and was titrated at the discretion of the treating physician.8,9 The use of cardiac resynchronization therapy (CRT) and implantable cardioverter defibrillator (ICD) according cur-rent guidelines were recorded.10,11 Clinical data were
collected in the Cardiology Department Information Sys-tem (EZIS chipsoft & EPD-Vision; Leiden University Med-ical Center, Leiden, The Netherlands).
Transthoracic echocardiography was performed in patients at rest in the left lateral decubitus position using commercially available ultrasound systems (Vivid 7 and E9; General Electric Vingmed, Horten, Norway). Data acquisition was performed with 3.5-MHz or M5S trans-ducers. Standard M-mode, 2D, color, pulsed, and continu-ous wave Doppler images were acquired and stored digitally for subsequent offline analysis (EchoPac BT13; GE Medical Systems, Horten, Norway). The LVEF was calculated in the apical 4- and 2-chamber views using the Simpson’s biplane method.12The wall motion score index was defined as the total sum of the segmental scores divided by the number of segments scored.12 In addition, LV dia-stolic function was assessed with transmitral flow pulsed-wave recordings and the peak early (E) and late (A) dia-stolic velocities as well as the E-wave deceleration time
was measured. The measurement of Ewas performed with tissue Doppler imaging at the septal location of the mitral annulus in the apical 4-chamber view. In addition, valvular morphology and function were assessed with 2D, color and pulsed and continuous wave Doppler echocardiography fol-lowing contemporary recommendations.13
Continuous variables with normal distribution are reported as mean § standard deviation and were analyzed using one-way analysis of the variance. Non-normally dis-tributed data are presented as median and interquartile range (IQR) and were analyzed with Kruskal-Wallis test. Categorical variables are reported as frequencies and per-centages and were analyzed using the chi square test. Uni-and multivariable regression analyses were performed to examine independent correlates of LVEF recovery at 6 months follow-up. Variables with p values < 0.2 on uni-variable analysis were included in the multiuni-variable analy-sis. Statistical analysis was performed on SPSS for Windows v23.0 (IBM, Armonk, New York). A 2-tailed p value< 0.05 was considered statistically significant. Results
A total of 371 (13%) patients of 2,853 patients admitted with acute STEMI had an LVEF ≤ 40% within 48 hours of admission. The mean age of the patient population was 61 § 12 (range 33 to 88) years and 76% were men (Table 1). The culprit lesion was the left anterior descending coronary artery in 236 (64%) patients and 214 (58%) presented with multivessel disease. The median levels of peak troponin T and creatine phosphokinase (CPK) were 6.5mg/L (IQR 3.2 to 12.3) and 2,564 U/L (IQR 1,253 to 4,671), respectively. At discharge, all patients received antiplatelet therapy, 99% of patients were treated with ACEi or ARB-II, 94% received b-blockers, 99% statins, 13% diuretics, and 6% received aldosterone antagonists. During the 6 months fol-low-up after index admission, 64 patients received heart failure device therapy: 37 (10%) received CRT and 24 (6.5%) an ICD.
Echocardiographic data within 48 hours of admission are presented inTable 2. The median LVEF was 36% (IQR 32 to 39) and the wall motion score index was 1.7 § 0.35. Moderate to severe mitral regurgitation was observed in 57 (15%) patients.
At 6 months follow-up, 115 (31%) patients did not show LV systolic function recovery and the LVEF remained ≤ 40%, 111 (30%) patients showed partial recovery (LVEF 41% to 49%) and 145 (39%) patients showed full recovery (LVEF ≥ 50%). Furthermore, there were no significant dif-ferences in age, gender, and prevalence of cardiovascular risk factors across the 3 groups (Table 1). Patients who showed full LVEF recovery had significantly lower fre-quency of anterior STEMI, smaller infarct size as indicated by the lower peak CPK and troponin T levels and shorter delay from onset symptoms to balloon inflation compared with the other groups. There were no differences regarding the usage of ACEi, ARB-II, b-blockers, statins, and anti-platelet therapy across the groups. However, patients with-out recovery of LVEF used more frequently diuretics and aldosterone antagonists and consequently received more frequently CRT and ICD devices (Table 1).
In terms of baseline echocardiographic characteristics, patients who showed full LVEF recovery had significantly smaller LV volumes and higher LVEF within 48 hours of admission as compared with the other groups (Table 2). Furthermore, patients with recovered LVEF had lower val-ues of wall motion score index and less frequently showed significant mitral regurgitation compared with the other groups (Table 2).
Uni- and multivariable analyses were performed to eval-uate the correlates of full LVEF recovery (≥ 50%) at 6 months follow-up. CRT was introduced as interaction term of time of implantation (median 9 days, IQR 7 to 28 days). On univariable analysis, peak troponin T levels, baseline LVEF, and significant mitral regurgitation were signifi-cantly correlated with LVEF recovery. On multivariable analysis, lower peak troponin T levels (odds ratio [OR]: 0.895; p < 0.001), baseline LVEF (OR 1.069; p = 0.023) and absence of significant mitral regurgitation (OR 0.376; p = 0.018) were independently associated with normaliza-tion of LVEF (≥ 50%) at 6 months follow-up, whereas guideline-based medications were not (Table 3).
Discussion
The prevalence of severe LV systolic dysfunction (LVEF ≤ 40%) after STEMI has reduced significantly with the systematic use of primary PCI.8,9,14−16The prevalence of severe LV systolic dysfunction in large series of patients with STEMI treated with primary PCI is approximately 20%.17,18 In a study including 216 patients with STEMI treated with primary PCI, Stolfo et al reported a prevalence of LVEF ≤ 40% of 19%.17 In addition, in a multicenter study of 3,798 STEMI patients treated with primary PCI, the prevalence of an LVEF ≤ 35% was 20%.18In the pres-ent study, the prevalence of LVEF ≤ 40% was 13%; this lower prevalence of LV systolic dysfunction compared with previous studies can be explained by different popula-tions: the aforementioned studies included older patients, with higher prevalence of co-morbidities and previous myocardial infarction as well as less strict use of cardiovas-cular medication recommended in current guidelines.8,9 Furthermore, ischemic preconditioning before PCI, pres-ence or abspres-ence of collateral flow and onset of reperfusion time are important factors influencing infarct size that have not been taken into consideration systematically in all stud-ies. LV functional recovery and remodeling is a continuous process influenced by several factors including location of the culprit lesion and area at risk, timing of revasculariza-tion, loading conditions, and medication.19
received b-blockers, while use of aldosterone antagonists was not reported. Conversely, in the present study patients were treated systematically according to guidelines, achiev-ing ≥ 94% use of ACEi, ARB-II, and b-blockers. This may have resulted in larger percentage of patients with an improvement in LVEF >40% at 6 months follow-up as compared with previous studies.17,20 In addition, in previ-ous studies there was probably less emphasis on the impor-tance of adherence to guideline-based therapy.17,20
Several factors have been associated with LVEF improvement in STEMI patients after primary PCI. The peak troponin level is an adequate reflector of infarct size as assessed with imaging techniques such as single-photon emission computed tomography and late gadolinium
contrast-enhanced cardiovascular magnetic resonance.21−23 Large areas of myocardial infarction are associated with impaired LVEF. In a study of 378 patients with STEMI treated with primary PCI, peak troponin levels showed a good sensitivity to predict a reduced LVEF ≤ 40% at 5-day and 30-day follow-up.5The present study showed an inde-pendent association between high peak troponin levels and lack of LVEF recovery at 6 months follow-up. Further-more, the presence of multivessel disease and the use of complete revascularization versus PCI of only the infarct-related artery may impact on the LV functional recovery. In a previous article of our STEMI cohort, Dimitriu-Leen et al showed that the presence of myocardial ischemia at 3 months after PCI was associated with more impaired LV
Table 1
Baseline characteristics for the entire study population
LVEF at 6 months follow-up
Variable Total population
(n = 371) No recovery (LVEF≤ 40%) (n = 115) Partial recovery (LVEF 41%−49%) (n=111) Full recovery (LVEF≥ 50%) (n = 145) p value Age (years) 60.5§ 12.2 60.4§ 12.3 60.0§ 12.8 61.0§ 11.6 0.815 Men 280 (76%) 88 (77%) 84 (76%) 108 (75%) 0.929
Heart rate discharge (bpm) 74§ 13 76§ 14 73§ 12 74§ 13 0.130
Systolic blood pressure (mm Hg) 135§ 26 131§ 27 136§ 23 137§ 27 0.197
Diastolic blood pressure (mm Hg) 82§ 17 81§ 17 82§ 16 82§ 18 0.625
Body surface area (m2) 2.0§ 0.26 2.0§ 0.3 2.0§ 0.3 2.0§ 0.2 0.475
QRS duration (ms) 90 (80-100) 90 (80-100) 92 (80-100) 90 (90-100) 0.743
Hypertension, n(%) 119 (32%) 37 (32%) 40 (36%) 42 (29%) 0.354
Hypercholesterolemia, n(%) 60 (16%) 20 (33%) 17 (28%) 23 (38%) 0.506
Family history of CAD, n(%) 172 (46%) 57 (49%) 49 (44%) 66 (46%) 0.940
Diabetes mellitus, n(%) 52 (14%) 18 (16%) 17(15%) 17 (12%) 0.747 Current smoker, n(%) 177 (48%) 48 (42%) 59 (53%) 70 (48%) 0.428 Peak CPK (U/L) 2564 (1253−4671) 4587 (2348−6118) 3015 (1373−4416) 1500 (872−2581) <0.001 Peak cTnT (mg/L) 6.5 (3.2−12.3) 10.7 (6.3−16.8) 6.8 (3.0−12.4) 4.4 (2.4−7.4) <0.001 eGFR (ml/min/1.73m2) 97§ 34 101§ 37 99§ 32 93§ 33 0.202 Coronary angiography Killip class≥ 2 23 (6%) 10 (9%) 3 (3%) 10 (7%) 0.083 TIMI flow 2−3 361 (98%) 112 (98%) 109 (98%) 140 (97%) 0.539 Culprit vessel, n(%) Right 92 (25%) 12 (10%) 28 (25%) 52 (36%) <0.001 Left main 2 (1%) 0 (0%) 1 (1%) 1 (1%) <0.001
Left anterior descending 237(64%) 95 (83%) 68 (61%) 74 (50%) <0.001
Left circumflex 40 (10%) 8 (7%) 14 (13%) 18 (12%) <0.001
Multi-vessel disease 214 (58%) 73 (64%) 65 (59%) 76 (52%) 0.317
Time to balloon inflation (minutes) 180 (131−290) 202 (150−352) 190 (135−323) 153 (115−218) 0.020 Medication at discharge, n (%) ACEi/ARBs 367 (99%) 114 (99%) 109 (98%) 144 (99%) 0.671 Antiplatelet 371 (100%) 115 (100%) 111 (100%) 145 (100%) 0.328 b-blockers 350 (94%) 109 (95%) 103 (93%) 138 (95%) 0.695 Statins 366 (99%) 113 (98%) 110 (99%) 143 (99%) 0.861 Diuretics 48 (13%) 30 (26%) 7 (6%) 11 (8%) <0.001 Aldosterone antagonists 21 (6%) 15 (13%) 1 (1%) 5 (3%) <0.001 Device therapy, n(%)
Cardiac resynchronization therapy 37 (10%) 25 (22%) 8 (7%) 4 (3%) <0.001
Implantable cardioverter defibrillator 24 (6.5%) 17 (15%) 4 (4%) 3 (2%) <0.001
systolic function.24 In addition, baseline LVEF is also an important determinant of the improvement in LV systolic function at follow-up. LVEF is strongly associated with myocardial infarct size: a low LVEF reflects larger damage that may not recover at follow-up. Oh et al investigated pre-dictors of LV functional recovery (LVEF ≥ 45%) in 1,307 patients after myocardial infarction (STEMI; n = 913 and non-STEMI; n = 394).25In a multivariable model, individu-als with a baseline LVEF (≥ 30 and <45%) had higher probability (OR 1.73; p = 0.013) of improvement in LVEF ≥ 45% after a median follow-up of 208 days as compared with patients with a baseline LVEF<45% (n = 644). These data are similar to the current findings where baseline LVEF was also independently associated with full recovery of LVEF at 6 months follow-up. Furthermore, loading con-ditions influence the LV remodeling process after STEMI.
Ischemic mitral regurgitation is a postinfarct complication that may occur in up to 64% of patients.26In a large con-temporary STEMI population (n = 1599), Abate et al reported a prevalence of 40% for ischemic mitral regurgita-tion in which 6% showed moderate and severe mitral regur-gitation after STEMI.27The LV volume overload imposed by mitral regurgitation may lead to larger LV volumes and more impaired LVEF preventing LV functional recovery.
How guideline-based medication influences LVEF recovery at follow-up has not been studied extensively in STEMI patients treated with primary PCI. Previous studies including only STEMI patients have reported lower usage of ACEi, ARB-II, andb-blockers.17,20In the present study, including a large population homogeneously treated in terms of ACEi, ARB-II, and b-blockers, an independent association between the use of these therapies and LVEF
Table 2
Baseline echocardiographic characteristics for the entire study population
LVEF at 6 months follow-up
Variable Total population
(n = 371) No recovery (LVEF≤ 40%) (n = 115) Partial recovery (LVEF 41%−49%) (n = 111) Full recovery (LVEF≥ 50%) (n = 145) p value LV mass index (g/m2) 113§ 33 118§ 35 110§ 31 112§ 33 0.190 LV end-diastolic volume (ml) 107 (87−136) 117 (101−148) 108 (92−141) 101 (77−118) <0.001 LV end-systolic volume (ml) 70 (56−89) 80 (64−101) 70 (58−90) 64 (49−76) <0.001 LV ejection fraction (%) 36 (32−39) 35 (29−38) 36 (32−39) 37 (34−39) 0.003
Wall motion score index 1.7§ 0.35 1.8§ 0.38 1.7§ 0.30 1.6§ 0.31 <0.001
Significant mitral regurgitation*, at baseline 57 (15%) 36 (32%) 12 (11%) 9 (6%) <0.001
E-wave velocity (cm/s) 62§ 18 62§ 19 62§ 18 61§ 17 0.710
A-wave velocity (cm/s) 70§ 20 70§ 21 71§ 18 69§ 21 0.631
E-prime (cm/s) 5.0§ 1.9 4.5§ 1.6 5.2§ 1.9 5.2§ 2.0 0.008
E/A ratio 0.95§ 0.4 0.95§ 0.4 0.92§ 0.4 0.96§ 0.4 0.771
Deceleration time (ms) 230§ 730 186§ 81 321§ 1333 195§ 68 0.295
Data are presented as mean§ standard deviation, number (percentage) or as median (25th−75th percentile). LV = left ventricular; LVEF = left ventricular ejection fraction. p values are presented for the comparisons between the different types of groups.
* Significant mitral regurgitation was defined as moderate or severe mitral regurgitation.
Table 3
Uni- and multivariable analyses to investigate independent correlates of left ventricular function recovery at 6 months follow-up
Variable Univariable analysis Multivariable analysis
Odds ratio 95% CI p value Odds ratio 95% CI p value
Age (years) 1.005 0.988−1.023 0.550 — — — Men 0.916 0.566−1.485 0.723 — — — ACEi/ARBs, at discharge 1.937 0.200−18.808 0.569 — — — b-blockers, at discharge 1.302 0.512−3.07 0.579 — — — Statins, at discharge 0.962 0.159−5.828 0.966 — — — Aldosterone antagonists 0.957 0.386−2.369 0.942 — — —
Cardiac resynchronization therapy* — — — 0.995 0.990−1.001 0.106
LAD as culprit vessel 0.403 0.260−0.623 <0.001 0.668 0.413−1.080 0.100
Three-vessel disease 0.957 0.577−1.588 0.865 — — —
Peak troponin level (mg/L) 0.872 0.834−0.913 <0.001 0.895 0.854−0.939 <0.001
Heart rate, at discharge (bpm) 0.992 0.976−1.009 0.346 — — —
LVEF, at baseline (%) 1.103 1.049−1.160 <0.001 1.069 1.009−1.133 0.023
Significant mitral regurgitationy, at baseline 0.246 0.117−0.519 <0.001 0.376 0.168−0.844 0.018 ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blocker; bpm = beats per minute; LAD = left anterior descending coronary artery; LV = left ventricular; LVEF= left ventricular ejection fraction.
recovery was not observed. This underscores the impor-tance of systematic approach of patient care following pre-vailing guidelines which is strongly advocated.
Several limitations should be acknowledged. The pres-ent study was retrospective. Levels of troponin T and CPK may not be the perfect reflector of myocardial infarct size. Data on late gadolinium contrast-enhanced cardiac mag-netic resonance were not systematically available. Finally, LVEF changes were assessed at 6 months follow-up. Sub-sequent changes leading to recovery of LVEF were not assessed.
Disclosures
The authors have no conflicts of interest to report.
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