Percutaneous coronary intervention in acute myocardial infarction: from
procedural considerations to long term outcomes
Delewi, R.
Publication date
2015
Document Version
Final published version
Link to publication
Citation for published version (APA):
Delewi, R. (2015). Percutaneous coronary intervention in acute myocardial infarction: from
procedural considerations to long term outcomes. Boxpress.
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Chapter 9
long term myocardial recovery after
revascularization for ST-segment elevation
myocardial infarction as assessed by cardiac
magnetic resonance imaging
Ronak Delewi, Mariëlla E.C.J. Hassell, Alexander Hirsch, Robin Nijveldt, Lourens Robbers, Jan G.P. Tijssen, Albert C. van Rossum, Felix Zijlstra, Jan J. Piek
ABSTRACT
BACkGROUND
Left ventricular remodeling following ST-segment elevated myocardial infarction (STEMI) is an adaptive response to maintain the cardiac output despite myocardial tissue loss. Limited studies have evaluated long term ventricular function using cardiac magnetic resonance imaging (CMR) after STEMI. The present study assesses the long term functional outcome in STEMI patients treated by primary percutaneous coronary intervention (PCI).
METHODS
Study population consisted of 155 primary PCI treated first STEMI patients. CMR was performed at 4 ± 2 days, 4 months and 24 months follow-up. Patients were treated with beta-blockers, ACE- or AT-II- inhibitors, statins and dual antiplatelet during follow-up according to current international guidelines.
RESUlTS
Mean left ventricular ejection fraction (LVEF) at baseline was 44±8%. Twenty-one percent of the study population had an increase of more than 5.0 % between 4 months and 24 months of follow-up and 21% of the cohort had a decrease of more than 5.0 % , indicating that left ventricular function is still dynamic, even after 4 months. Patients with long term LVEF deterioration have significantly larger end systolic volumes at 24 months than patients with improvement of LVEF (61±23ml/m2 compared to 52±21ml/ m2, p=0.02) and less wall thickening in the remote zone. Whereas, patients with left ventricular improvement had significantly greater improvement in wall thickening in the infarct areas, but also in the non-infarct or remote zone.
CONClUSION
Contrary to previous studies, we demonstrate that myocardial remodeling is a long-term process continuing up to 24 months post-PCI in STEMI patients. Long long-term LVEF deterioration is characterized by an increase in end systolic volume and less wall thickening in the remote zones. Patients with LVEF improvement exhibit an increase in left ventricular wall thickening both in the infarct as well as in the remote zones.
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INTRODUCTION
Myocardial recovery after revascularization for ST-segment elevation myocardial infarction (STEMI) is a major determinant for the short and long term clinical outcome.1 Left ventricular (LV) remodeling may transit from an apparently compensatory process to a maladaptive one leading to heart failure.2 When remodeling occurs, the entire heart can be involved, as disproportionate thinning and dilation in the infarct region (i.e. infarct expansion) is accompanied by a distortion in shape of the entire heart with volume-overload hypertrophy of the noninfarcted myocardium.3
Cardiac magnetic resonance (CMR) has emerged as a valuable clinical and research tool after acute STEMI. It represents the gold standard for functional and morphological evaluation of the LV.4 The resolution of gadolinium-based perfusion and late-enhancement viability imaging allows a detailed analysis of the pathophysiology of inadequate myocardial recovery. However, to date there is limited CMR data assessing long term left ventricular function providing more insight in which patients are more prone to develop adverse remodeling. The purpose of this study was to evaluate the early (baseline – 4 months) and late remodeling process (4-24 months) assessed by CMR.
METHODS
Study population
The study population consisted of STEMI patients included in the HEBE study, a multicenter, randomized, trial assessing intracoronary bone marrow cell therapy. The details of the design and results have been published previously5. CMR imaging was performed at baseline, 4 months and 2 years of follow-up. Patients with a history of myocardial infarction were not included in this study. There were no significant differences between the two treatment groups and the control group at baseline. All patients were treated with primary percutaneous coronary intervention (PCI) with stent implantation within 12 hours of symptom onset. Patients were treated with aspirin, heparin and P2Y12 inhibitor according to American College of Cardiology/American Heart Association practice guidelines. At discharge, 95% were treated with β-blockers, 99% with statins and 93% with angiotensin-converting-enzyme (ACE) or angiotensin inhibitors (AT II inhibitors).
Of the 200 patients that originally enrolled in the HEBE study, at 24 months 1 had withdrawn informed consent, 3 had died, 3 did not consent to this additional long-term follow-up and 3 were lost to follow-up. At 24 months, 19 patients had clinical follow-up but did not undergo CMR because of implantable cardioverter-defibrillator implantation (n=8), pacemaker implantation (n=1) or because they refused (n=10). Additionally, 12
patients were excluded from core lab analysis due to one of the following reasons: poor quality due to breathing or triggering artefacts, or baseline, 4 months and 24 months CMR could not be matched. Of the remaining 159 patients, 4 patients had a recurrent myocardial infarction in the 2 years of follow-up, and were also excluded from the analysis, because this clearly has influence on the remodeling process.
Cardiac magnetic resonance imaging
Patients were studied on a clinical magnetic resonance scanner (Siemens, Erlangen, Germany; Philips, Best, the Netherlands; GE Healthcare, Buckinghamshire, UK). The CMR protocol at 24 months was similar to the CMR protocol at baseline and 4 months, with the exception that no contrast medium was administrated to assess infarct size and transmural extent. At baseline and at 4 months late gadolinium enhancement (LGE) was done 10 to 15 minutes after administration of a gadolinium-based contrast agent (Dotarem, Guerbet, Roissy, France; 0.2 mmol/kg) with a 2-dimensional segmented inversion recovery gradient-echo pulse sequences. Typical in-plane resolution was 1.4 × 1.7 mm2, with a slice thickness of 5.0 to 6.0 mm (repetition time/echo time = 9.6/4.4 ms, flip angle 25º, triggering to every other heartbeat). Inversion time was set to null the signal of viable myocardium.
Moreover, at every time point contiguous short axis slices were acquired every 10 mm covering the whole LV using a cine retrospectively ECG-gated segmented steady state free precession pulse sequence, with image parameters identical to the scan. LV volumes were measured on the cine images and indexed for body-surface area. Left ventricular ejection fraction (LVEF) was calculated following assessment of left ventricle end diastolic volume (LVEDV) and left ventricle end systolic volume (LVESV).
For analysis of regional myocardial function, each short axis slice was divided in 12 equiangular segments to calculate wall thickening (in mm) of each segment by subtracting end-diastolic from end-systolic wall thickness. Segmental wall thickness was measured at end-systole and end-diastole after manual tracing of endocardial and epicardial borders in stop-frame images, excluding trabeculations and papillary muscles. The contours were drawn blinded to patient identity, clinical history, and scan time point. Segmental wall thickness was calculated as the average of the chords within one segment.
All CMR analyses were performed in a core laboratory using a standardized protocol. Both baseline and 4 months follow-up scan were used to match all three CMR imaging for slice position using anatomic landmarks, such as papillary muscles and right ventricular insertion sites.
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Statistical analysis
Categorical data are presented as frequencies (percentage) and continuous data as mean ± SD. The study population was divided in a group with LVEF improvement and LVEF deterioration. LVEF improvement was defined as any increase of LVEF between 4months and 24 months. LVEF deterioration was defined as no improvement of LVEF, or a decrease in LVEF. Univariate and subsequent multivariate analysis was performed to assess which clinical characteristics were associated with long-term remodeling (change between 4 and 24 months). In the multivariate analysis, treatment as randomized in the HEBE trial was always entered as a covariate (intracoronary injection of mononuclear bone marrow cells or peripheral blood cells or control).
Segmental CMR analysis was used to gain more insight in this long-term remodeling process. Improvement in wall thickening (in mm) between 4 months and 24 months of follow-up was used to assess differences of infarct transmurality and subsequent positive or adverse LVEF changes. To account for non-independence of the data, we used multilevel logistic to analyze the relation between wall thickening and improvement of LVEF. We performed multilevel analysis (segments within slices clustered within patients). All p values are two-sided and statistical significance was set at p<0.05. Statistical analysis was done with the Statistical Package for Social Sciences software (SPSS 21.0 for Windows).
RESUlTS
The final study population consisted of 155 patients, with an average age of 56 years. At discharge, 95% of the study population received ACE-inhibitors or angiotensin II receptor antagonist at discharge and 94% percent β-blockers. Mean LVEF at baseline was 44±8%, at 4 months 48±9%, and at two year follow-up 48± 9%.
Early remodeling (baseline - 4 months)
During the initial 4 months we observed a mean LVEF increase of 4±7%. Twenty-one percent of the study population had an increase of more than 5.0 % after 4 months of follow-up and 21% of the cohort had a decrease of more than 5.0 % , indicating that left ventricular function is dynamic.
Late remodeling (4 – 24 months)
Between 4 months and 24 months of follow-up a mean LVEF increase was 0 ± 7%. Compared to early remodeling, the distribution in delta LVEF was the same for late remodeling between 4 and 24 months (Figure 1). Patients with LVEF deterioration had a significantly larger LVESV at 24 months compared to the group with LVEF
improvement (61±23ml/m2 compared to 52±21ml/m2, p=0.02), with no differences in LVEDV (Table 2).
No clinical, demographical, electrocardiographic or CMR parameters were predictive for the change of LVEF between 4 months and 24 months in univariate linear regression model. However, patients with LVEF improvement more often had β-blockers usage at 24 months (96% versus 80%, p=0.004), and higher systolic blood pressure at 4 months (130±21mmHG compared to 122±17mmHG, p=0.01) compared to patients with LVEF deterioration, Table 3).
Segmental wall thickening and remodeling
In segmental CMR analysis, we assessed absolute wall thickening in mm per segment in a 12-segments model and categorized these segments according to the percentage LGE. Change in wall thickening (mm) was significantly greater in patients with LVEF improvement compared to patients with LVEF deterioration (Figure 2). Particularly, in segments with 0% or 1-25% LGE, the so called no-infarct or remote zone, this change in wall thickening was greater in patients with LVEF improvement compared to patients with LVEF deterioration.
Figure 1 Change in left ventricular ejection fraction (%) as assessed by cardiac magnetic resonance
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Table 1 Baseline characteristics for study population
N=155 Age (years) 56±9 Male gender 132 (85%) Diabetes mellitus 9 (6%) Known hypertension 47 (30%) Hypercholesterolemia 29 (19%)
Current cigarette smoking 79 (51%)
Time from symptom onset to PCI (hours) 3.3 (2.2–4.5)
Anterior infarction 98 (63%)
Medication at discharge
ACE-inhibitors/AT-II antagonists
β-blockers 147 (95%)146 (94%) Cardiac Magnetic Resonance imaging
LVEF (%)
LV end Diastolic Volume (ml/m2)
LV end Systolic Volume (ml/m2)
44±8 98±16 56±14 Infarct size (gram) ‡ 22±12 Presence of microvascular obstruction 90 (58%)
‡ analysis available in 132 patients ACE; angiotensin-converting-enzyme inhibitor, AT; Angiotensin, LVEF; left ventricular ejection fraction, LV; left ventricular; PCI; percutaneous coronary intervention
Table 2 Cardiac magnetic resonance imaging parameters for study population split for change in
left ventricular ejection fraction between 4 months and 24 months of follow-up
long-term remodeling (4 – 24 months) lVEF improvement
(n=78) lVEF deterioration (n=77) P-value
LVEF (%) 4±2 days 4 months 24 months LVEDV (ml/m2) 4±2 days 4 months 24 months LVESV (ml/m2) 4±2 days 4 months 24 months 45±9 46±8 51±9 98±16 104±22 104±26 57±14 57±14 52±21 43±8 50±9 44±8 98±15 104±22 107±25 57±14 54±15 61±23 0.07 0.007 0.001 0.85 0.96 0.47 0.30 0.27 0.02 Infarct size (gram) ‡ at 3-5 days
Presence of MVO at 3-5 days 21±13 42 (54%) 22±12 48(63%) 0.620.33
LVEF=Left ventricular ejection fraction (%); LVEDV=left ventricular end diastolic volume; LVESV=left ventricular end systolic volume, MVO=microvascular obstruction.
Table 3 Study population split for change in left ventricular ejection fraction between 4 months
and 24 months of follow-up as assessed by cardiac magnetic resonance imaging
long-term remodeling (4 – 24 months) lVEF improvement
(n=78) lVEF deterioration (n=77) P-value
Age (years) 57±10 54±9 0.04
Male gender 64 (82%) 68 (88%) 0.36
Diabetes mellitus 5 (6%) 4 (5%) 1.00
Known hypertension 27 (35%) 20 (26%) 0.30
Hypercholesterolemia 16 (21%) 13 (17%) 0.68 Current cigarette smoking 37 (47%) 42 (55%) 0.42 Time from symptom onset to PCI (hours) 3.5 (2.2–4.5) 3.2 (2.2–4.3) 0.57
Anterior infarction 52 (67%) 46 (60%) 0.41 ACE-inhibitors/AT-II antagonists discharge 4 months 12 months 24 months Beta-blockers 71 (91%) 72 (92%) 72 (92%) 73 (94%) 76 (99%) 74 (96%) 69 (90%) 67 (87%) 0.06 0.50 0.78 0.40 discharge 73 (94%) 73 (95%) 1.00 4 months 12 months 24 months
Systolic blood pressure (mmHg) discharge
4 months 12 months 24 months
Diastolic blood pressure (mmHg) discharge 4 months 12 months 24 months Heart rate (bpm) discharge 4 months 12 months 24 months 72 (92%) 74 (95%) 75 (96%) 115±16 130±21 127±19 130±21 72±12 79±11 77±10 78±13 71±12 64±10 65±14 63±12 69 (90%) 69 (90%) 61 (80%) 113±14 122±17 124±18 124±19 69±10 77±10 77±10 75±13 71±10 62±11 63±10 63±10 0.59 0.37 0.004 0.33 0.01 0.40 0.10 0.10 0.14 0.58 0.08 0.80 0.45 0.18 0.89
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-1 -0,8 -0,6 -0,4 -0,2 0 0,2 0,4 0,6 0,8 1 LVEF improvement LVEF deterioration P<0.001 P=0.36 P=0.27 P=0.002 P<0.001LGE 0% LGE 1- 25% LGE 26-50% LGE 51-75% LGE 76-100%
Delta
w
all
thickening
(mm)
Figure 2 Change in segmental wall thickening (in mm) between 4 and 24 months follow-up as
assessed by cardiac magnetic resonance imaging categorized for percentage of late gadolinium enhancement (LGE) and split for patients with left ventricular ejection fraction improvement or deterioration between 4 and 24 months
DISCUSSION
The present study assesses the long term functional outcome of STEMI patients treated with primary PCI and subsequent pharmacological therapy. The main findings can be summarized as follows: 1) left ventricular function improvement after acute myocardial infarction is a dynamic process and ongoing up to 2 years follow-up, 2) long-term LVEF deterioration is characterized by an increase in end systolic volume and less wall thickening in the remote zones, 3) patients with long-term LVEF improvement exhibit an increase in left ventricular wall thickening both in the transmural infarct and remote zones.
In the current study we demonstrate that left ventricular remodeling is a long term process and is observed up to 24 months after STEMI. To our knowledge, there are no other CMR studies that report the occurrence of long term remodeling at 2 years. A previous study by Segrestin et al also observed adverse remodeling up to 1 year following acute anterior myocardial infarction with increased end-diastolic volume as assessed by echocardiography.6 In accordance with our study, there was a systematic use of secondary prevention treatment with β- blockers and ACE inhibition to slow, or reverse cardiac remodeling after acute myocardial infarction. In our study, the only clear association between positive remodeling and pharmacotherapy was the use of beta- blocker at 24 months. Whether additional pharmacotherapy like the new class of angiotensin-neprilysin inhibitors can modulate the process of remodeling after PCI-treated STEMI yet needs to be established.7
Additionally to change in LVEDV, infarct healing with a decrease in infarct size has previously been reported up to 1 year following myocardial infarction. Although decrease in infarct size occurs rapidly within the initial 4 months, a further reduction can be observed in the following months8.
In the current study remodeling was not influenced by secondary ischemic events, as these patients were excluded from the analysis. Additionally, demographic, electrocardiographic and CMR variables were not associated with change in LVEF between 4 and 24 months. However, LVESV was significantly increased in patients with LVEF deterioration. End-systolic volume is influenced by both end-diastolic volume and myocardial contraction. In a prior study LVESV, has been reported as the strongest prognostic indicator for survival in post-STEMI patients.9
In the current study, no difference in infarct size was observed in patients that developed deterioration in LVEF between 4 and 24 months. However, as in previous studies, infarct size and the presence of microvascular injury at baseline are associated with
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the magnitude of left ventricular deterioration within the initial months following myocardial infarction 10, 11.
Initial remodeling in the first months after a myocardial infarction may, to some extent, be considered beneficial when associated with improvement or maintenance of LV function and cardiac output. However, it has been suggested that the long term remodeling process is driven by hypertrophic myocyte elongation in the non-infarcted zone, resulting in increase in wall mass and LV enlargement. This is accompanied by a shift from an elliptical to a more spherical chamber configuration 4, 12. These changes, together with a decline in performance of the pathologically hypertrophied myocyte and interstitial fibrosis within the noninfarcted zone, results in progressive decline in ventricular performance. This is in accordance with the current findings. We observed with segmental CMR analysis that patients with LVEF deterioration between 4 and 24 months follow-up had a significant decreased change in wall thickening compared to patients with LVEF improvement. This was observed both in the segments with transmural infarction (LGE 76-100%) and in the non-infarct or remote zone (LGE 0% and LGE 1-25%). Moreover, the observed change in wall thickening in patients with LVEF improvement or deterioration was not dependent on infarct size and was similar in both groups. Patients showing LVEF improvement showed a significant increased wall thickening in the transmural segments compared to patients with LVEF deterioration. This may suggest that the defined cut of value for viability (75% transmurality as assessed by CMR), is questionable as the infarct zone exhibits improvement at long term follow-up.
Thus, the results of the current study show that LV remodeling, both positive and negative, is an ongoing process and continues up to 2 years after STEMI, involving not only the infarct zone but also remote zones. Despite the fact that early remodeling may initially seem adaptive with early maintenance of cardiac output, this continuous remodeling process may only further deteriorate the LV with increased LV volumes and increased incidence of heart failure and cardiovascular death.
Limitations
In the current study patients with relatively large infarcts (elevation of creatine kinase-myocardial band > 10 times the upper limit of normal) were included. Therefore, the occurrence of adverse remodeling is likely higher than in a more general acute myocardial infarction population.
Moreover, in the current study the remodeling process was only assessed by functional parameters assessed by CMR. Despite its clinical and prognostic importance, we do not provide any additional insights on the remodeling process at the histological level.
CONClUSION
Cardiac remodeling is a dynamic and ongoing process up to 24 months following acute myocardial infarction. Long term LVEF deterioration is characterized by an increase in end systolic volume and less wall thickening in the remote zones. Patients with LVEF improvement exhibit an increase in left ventricular wall thickening both in the infarct as well as in the remote zones.
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