s
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 6
Myocardial infarct heterogeneity assessment by
late Gadolinium Enhancement Cardiovascular
Magnetic Resonance imaging shows predictive value
for ventricular arrhythmia development after acute
myocardial infarction
Ronak Delewi*, Lourens F.H.J Robbers*, Robin Nijveldt, Alexander Hirsch, Aernout M. Beek, Michiel J.B. Kemme, Yvette van Beurden, Anja M. van der Laan,
Pieter A. van der Vleuten, Rene´ A. Tio, Felix Zijlstra, Jan J. Piek, Albert C. van Rossum
*Both authors contributed equally to this manuscript
ABSTRACT
AIMSThe aim of this study was to assess the association between the proportions of penumbra-visualized by late gadolinium enhanced cardiovascular magnetic resonance imaging (LGE-CMR)-after acute myocardial infarction (AMI) and the prevalence of ventricular tachycardia (VT).
METHODS
One-hundred and sixty-two AMI patients, successfully, treated by primary percutaneous coronary intervention (PCI) underwent LGE-CMR after a median of 3 days (3-4) and 24-h Holter monitoring after 1 month. With LGE-CMR, the total amount of enhanced myocardium was quantified and divided into an infarct core (>50% of maximal signal intensity) and penumbra (25-50% of maximal signal intensity). With Holter monitoring, the number of VTs (≥4 successive PVCs) per 24 h was measured.
RESUlTS
The mean total enhanced myocardium was 31 ± 11% of the left ventricular mass. The % penumbra accounted for 39 ± 11% of the total enhanced area. In 29 (18%) patients, Holter monitoring showed VT, with a median of 1 episode (1-3) in 24 h. A larger proportion of penumbra within the enhanced area increased the risk of VTs [OR: 1.06 (95% CI: 1.02-1.10), P = 0.003]. After multivariate logistic regression analysis, the presence of ventricular fibrillation before primary PCI [OR: 5.60 (95% CI: 1.54-20.29), P = 0.01] and the proportional amount of penumbra within the enhanced myocardium [OR: 1.06 (95% CI: 1.02-1.10), P = 0.04] were independently associated with VT on Holter monitoring.
CONClUSION
Larger proportions of penumbra in the subacute phase after AMI are associated with increased risk of developing VTs. Quantification of penumbra size may become a useful future tool for risk stratification and ultimately for the prevention of ventricular arrhythmias.
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INTRODUCTION
Ventricular arrhythmias, ventricular tachycardia (VT) and ventricular fibrillation (VF), are life-threatening complications of myocardial infarctions and are associated with increased post-myocardial infarction morbidity and mortality.1 More specifically, VTs
more than 48 hours after AMI, consisting of 4 successive beats or more, are associated with an increased prevalence of sudden cardiac death.2-4 Although several studies
already have already shown that prophylactic therapy with an implantable cardioverter-defibrillator (ICD) leads to an improved survival in patients with left ventricular (LV) dysfunction after a myocardial infarction,2,3,5 only approximately 35% of the patients
receive appropriate ICD therapy during the first 3 years of follow-up.6 For this reason,
additional risk stratification to identify the patients at risk of developing ventricular arrhythmias is necessary.
Prerequisites for the development of ventricular arrhythmias are an arrhythmogenic substrate, triggering factors and facilitating conditions.7 A suitable arrhythmogenic
substrate for ventricular arrhythmias contains a unidirectional pathway for re-entry, a short refractory period, and a decreased impulse conduction velocity. Myocardial infarction-induced scar tissue formation can induce these disturbances in the myocardium and their association with an increase in adverse events has already been shown.8,9 Although
the infarcted myocardium consists of non-viable, necrotic tissue, the surrounding border zone -or penumbra- consists of a heterogeneous collection of necrotic, ischemic and viable myocytes, oedema, and fibroblasts, which can theoretically provide suitable conditions for the development of arrhythmias.10,11
We hypothesize that in the subacute phase after revascularized AMI, a larger proportion of penumbra provides more suitable conditions for arrhythmogenesis and increases the susceptibility to ventricular arrhythmias. Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) is a safe, reliable and feasible non-invasive method of assessing and quantifying structural damage to the myocardium.12,13 This
study therefore investigates the association of the LGE-measured penumbra size around the infarcted area, and the development of VTs.
METHODS
Between August 2005 and April 2008 the HEBE trial was performed, in which 200 patients between 30 and 75 years old with a large first ST-elevated myocardial infarction, successfully treated with primary PCI, were included (14). This study is a selection of the patients from this trial. The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by Institutional Review Boards of the participating institutes. The HEBE study design and main results have been published previously.14,15
In short, all participating patients received standard medical therapy according to the current guidelines. After giving informed consent, the patients were randomly assigned in a 1:1:1 ratio to a control group (standard medical therapy only), or additional treatment with either intracoronary infusion of autologous bone marrow mononuclear cells (BMMC) or autologous peripheral blood mononuclear cells (PBMC). To evaluate the likelihood of increased ventricular arrhythmia after BMMC and PBMC infusion, resting electrocardiogram (ECG) and 24-hour ambulant ECG recording (Holter monitoring) were acquired 1 month after primary PCI. In addition, clinical follow-up data were obtained at 4 and 12 months, consisting of clinical status and the occurrence of major adverse events (i.e. cardiac death or severe arrhythmic events). A severe arrhythmic event was defined as any event consisting of either sudden cardiac death or documented ventricular arrhythmias for which external defibrillation or implantable cardioverter-defibrillator (ICD) therapy was required. We have previously demonstrated that cell infusion does not predispose to ventricular arrhythmia or unfavourable outcome.16 In
this study, we evaluated the prevalence of VTs in relation to cardiac function and CMR-measured infarct tissue characteristics.
Cardiac magnetic resonance imaging
In all participating patients, CMR was performed between 2 and 7 days after PCI in a clinical 1.5 T MR-scanner (Siemens, Erlangen, Germany; Philips, Best, the Netherlands; GE Healthcare, Waukesha (WI), United States) with the use of a phased array cardiac receiver coil. Functional imaging was performed by using retrospectively ECG-gated steady-state free precession cine imaging with breath-holding. Standard 3 long-axis images (four-, three- and two-chamber view) and short-axis images with full-LV coverage were obtained (pixel size 1.6 x 1.9 mm, slice thickness 6.0 mm, slice gap 4.0 mm, TR/TE 3.2/1.6 ms, flip angle 60º, field of view 256 x 156 mm, TR 35 - 50 ms).
After administration of 0.2 mmol/kg Gd-DOTA (Guerbet, Villepinte, France), LGE images were acquired after 10-15 minutes, using a 2-dimensional segmented inversion-recovery gradient-echo pulse sequence, with individual correction of the inversion time
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to null the signal of normal myocardium (slice thickness 6.0 mm, slice gap 4.0 mm, field of view 360x360 mm, pixel size 1.4x1.4 mm, TR 1250 ms, typical inversion time 250-400ms). Cine and LGE images of each patient were matched by slice position.
Analysis and definitions of CMR parameters
Analysis was performed with dedicated off-line software (MASS v.5.1 2010-EXP beta, Medis, Leiden, the Netherlands). Cine images were analyzed as previously described for calculation of volumes and ejection fraction.14
Quantification of infarct core and the penumbra was performed on the short axis LGE images by an experienced CMR reader (YvB), blinded to all patient data and outcomes. In the Gadolinium-enhanced area, a region of interest (ROI) was drawn, containing the myocardium with visually the highest signal intensity, while avoiding any microvascular obstruction (MVO), due to its low signal intensity. A second ROI was drawn in an opposite, unenhanced area of myocardium without artefacts. Quantification was performed using the full-width at half-maximum (FWHM) technique.17,18 The
myocardial area containing gadolinium enhancement was divided into two regions. The myocardium with a signal intensity of >50% of the maximal intensity in the infarct area ROI, which is normally defined as the infarcted area,18 was defined as the infarct core.
The penumbra was defined as tissue located on the mesomyocardial or subepicardial side of the infarcted area, with an intensity of 25-50% of the maximal intensity in the infarct area ROI. The total enhanced area size is the summation of infarct core and penumbra; in regular myocardial infarct quantification, the penumbra is not included in the total infarcted area. MVO was defined as a subendocardial, hypointense recess of the myocardium within the enhanced area. When MVO was present, the infarct mass calculations were corrected for the presence of MVO by manually tracing the area of MVO to include it into the infarct core (figure 1). Tissue with intermediate signal intensity at the subendocardial border between MVO and the infarct core was manually assigned to the infarct core area.
The LGE parameters (i.e. amounts of infarct core, penumbra and total enhanced area) were divided by the total left ventricular mass to standardize the values. Secondly, the amounts of infarct core and penumbra were divided by the total amount of enhanced area to calculate the proportion of infarct core and penumbra within the total enhanced area.
Analysis and definitions of ECG and Holter monitoring
One month after primary PCI, 24-hour Holter monitoring was performed. Verification of the Holter data was performed by a different reader (LR), also blinded to all other patient data and outcomes. Analysis of rhythm and morphology (supraventricular or
ventricular) was performed for each individual complex. The total number of premature ventricular complexes (PVCs) and their configuration (single PVCs, doublet PVCs, triplet PVCs, non-sustained VTs and sustained VTs) were corrected for the total recording time, to standardize the mean number of arrhythmias per 24 hours. Any series of 4 or more successive ventricular complexes with a frequency of >100/min was marked as a VT. Together with the Holter monitoring, a resting 12-channel electrocardiogram (ECG) was made to measure QRS width and corrected QT-time (QTc). Simultaneously with the Holter monitoring, sodium and potassium levels were measured to assess whether serum electrolyte concentration disturbances influence the prevalence of ventricular arrhythmias.
Statistical analysis
First, we analyzed whether the treatment groups and control differed in functional and infarct size parameters and the amount of ventricular arrhythmias. Secondly, comparisons were made between the patients with and without ventricular arrhythmias for differences in functional and infarct size CMR parameters.
To assess which clinical and CMR parameters were independently associated with ventricular arrhythmias, multivariate analysis was performed. Variables with a p-value of p≤0.10 on univariate analysis, or a known relation with VTs (i.e. age, male gender, time between onset of symptoms and primary PCI, the presence of ventricular fibrillation before primary PCI, LAD-related infarction, LV EDVi, ESVi, EF, QRS width and QTc) were entered in a multivariate logistic regression model with a forward selection procedure; variables were entered if p<0.10. All P-values are two-sided and statistical significance was set at p<0.05.
Figure 1. Quantification of infarct core and penumbra using late gadolinium enhancement (LGE)
imaging.
Short axis mid-ventricular LGE image (A) with subendocardial microvascular obstruction (MVO, arrow) and quantification of infarct core and penumbra (B) using 25-50% and >50% FWHM cut-off values. Due to low signal intensity of MVO, manual delineation of MVO for inclusion in the infarct core was performed. Tissue with intermediate signal intensity at the border of MVO and the enhanced infarct core was manually assigned to the infarct core area as well.
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To investigate the relative prognostic importance and the interrelationship of different infarct parameters, the multivariate analyses were repeated, each time including different parameters. The predictive value of each of these models is expressed by the Nagelkerke R2 (i.e. as a measure of how well the observed outcomes are replicated by the model).
Statistical analysis was done with the Statistical Package for Social Sciences software (SPSS 15.0 for Windows).
RESUlTS
All patients with complete paired data sets of CMR and Holter registrations were included in the study. In 38 of the 200 patients, complete data sets were not available; 16 patients had missing CMR, 15 patients had missing Holter data, and in 7 patients, both data sets were missing. CMR data were unavailable due to lack of a CMR scan (n=6), insufficient image quality for cine or LGE analysis (n=15) or due to incorrect image acquisition (n=2). Holter data were missing in 22 cases; the data were either missing or not acquired (n=12), or of insufficient quality for analysis (n=10) due to severe artifacts or incomplete registration.
From the remaining 162 patients, 60 patients were randomized to BMMC treatment, 53 to PBMC treatment and 49 to the control group. CMR was performed at a median of 3 days [3-4 days] after primary PCI. Mean age was 56±10 years and 144 patients (87%) were male. The infarct related artery was the LAD in 64% of the cases, right coronary artery (RCA) in 25% and the LCx in 11%. The three treatment groups had similar baseline demographics, cardiovascular risk factors, medication, CMR and arrhythmia characteristics (Appendix 1).
During Holter monitoring at 1 month follow-up, 27 patients (17%) had triplet PVCs during the registration; of these 27 patients, 20 (74%) had monomorph triplets and 5 (19%) had polymorph triplets; in 2 patients (7%), the morphology could not be accurately established. Twenty-nine patients (18%) had VTs on Holter monitoring; of these 29 patients, 26 (90%) had monomorph VTs and 1 patient (3%) had polymorph VTs. In 2 patients (7%), the morphology was difficult to establish due to disturbances. Of all patients, 13 patients (8%) had both triplet PVCs and VT during registration. General characteristics, medication at discharge and characteristics of the Holter monitoring, blood chemistry and CMR of patients with and without VTs are described in table 1.
Cell therapy and arrhythmias
No difference in the prevalence of triplet PVCs was found between the BMMC group and the control group (15% versus 16%, p=0.85), or between the PBMC group and the control group (19% versus 16%, p=0.74) (16). Similarly, no differences were found in the prevalence of VTs between either the BMMC group and control (15% versus 18%,
Table 1. Baseline characteristics of patients with and without ventricular tachycardia. No Ventricular Tachycardia (n=133) Ventricular Tachycardia (n=29) p-value General parameters and risk factors
Age at primary PCI (years) 56 ± 10 56 ± 9 0.74
Body Mass Index (kg/m2) 26 ± 3 26 ± 4 0.38
Male gender 117 (88%) 24 (83%) 0.45
Diabetes 7 (5%) 0 (0%) 0.21
Hypertension 35 (26%) 7 (24%) 0.81
Family history of coronary artery disease 67 (50%) 13 (45%) 0.59
Hypercholesterolemia 30 (23%) 5 (17%) 0.53
Current smoking 70 (53%) 17 (59%) 0.56
PCI parameters
Time between onset of symptoms and primary PCI
(hours) 3 (2-5) 4 (2-5) 0.90
Presence of ventricular fibrillation before PCI 6 (5%) 6 (21%) 0.01
LAD* coronary related infarction 87 (65%) 16 (55%) 0.30
Platelet glycoprotein IIb/IIIa inhibitor administered 94 (71%) 19 (66%) 0.58
Medication at discharge in
Aspirin 129 (97%) 28 (97%) 1.00a
Clopidogrel 133 (100%) 29 (100%) n/a
Coumarin derivate 23 (17%) 5 (17%) 1.00
Beta blocker 127 (96%) 28 (97%) 0.80
ACE or Angiotensin-II inhibitor 125 (94%) 27 (93%) 0.86
Statin 132 (99%) 29 (100%) 1.00a
Holter monitoring and biochemical parameters at 1 month
Duration of Holter monitoring (hours) 24 (23-25) 24 (23-25) 0.98
QRS duration (ms) 94 (86-100) 96 (85-102) 0.64
Corrected QT interval (QTc) 420 ± 28 416 ± 26 0.43
Serum sodium level (mMol•l-1) 141 ± 2 142 ± 2 0.13
Serum potassium level (mMol•l-1) 4.4 ± 0.4 4.3 ± 0.3 0.77
Usage of beta-blocker 124 (93%) 28 (97%) 0.50
Functional and infarct mass parameters
LV indexed end-diastolic volume (ml•m-2) 97.7 ± 15.4 101.6 ± 16.7 0.23
LV indexed end-systolic volume (ml•m-2) 56.5 ± 14.9 59.4 ± 15.6 0.34
LVindexed stroke volume (ml•m-2) 41.2 ± 7.9 42.1 ± 8.5 0.59
LVejection fraction (%) 42.8 ± 8.7 42.0 ± 8.4 0.65
Presence of MVO 84 (63%) 12 (41%) 0.03
Percentage Enhanced myocardium of total LV mass 32% ± 11% 27% ± 12% 0.04
Percentage Core zone of total LVmass 20% ± 9% 15% ± 9% 0.01
Percentage Core zone of total enhanced myocardium 62% ± 11% 55% ± 11% 0.002
Percentage Penumbra of total LVmass 11% ± 4% 11% ± 5% 0.92
Percentage Penumbra of total enhanced myocardium 38% ± 11% 45% ± 11% 0.002
Core/Penumbra Ratio 1.9 ± 1.0 1.4 ± 0.6 0.01
LAD=left anterior descending artery; LV=left ventricle; MVO=microvascular obstruction; PCI=percutaneous coronary intervention.
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p=0.64) or between the PBMC group and control (21% versus 18%, p=0.76) (appendix 1).
Cardiac death and severe arrhythmic events
During 1 year follow-up, none of the 162 patients suffered from ventricular fibrillation (VF) and none of the 162 patients had died at 1 year. Three patients received an ICD for primary prevention according to the Guidelines of the European Society of Cardiology.19
None of the patients received an ICD for secondary prevention.
Of the 38 patients that were excluded due to incomplete data sets, 3 patients had a severe arrhythmic event. One patient of the PBMC group died of VF 13 days after cell therapy; autopsy revealed in-stent thrombosis. Two patients had documented VF and survived; one of these two patients was assigned to the PBMC treatment and developed VF a few hours after cell infusion. The other patient was assigned to the control group and VF occurred 3 days after randomization. After successful resuscitation without sequelae, both patients received an ICD implantation for secondary prevention. No other patients received an ICD. In none of the patients with an ICD, an appropriate ICD discharge was reported..
Infarct mass and penumbra
Patients had a mean total enhanced area size of 31±11% of the total left ventricular mass. Of the total LV mass, 19±9% consisted of infarct core and 11±4% consisted of penumbra. The total enhanced area consisted for 61±11% of infarct core and for 39±11% of penumbra. All the aforementioned infarct parameters were equally distributed amongst the treatment groups (appendix 1).
Patients with VTs had a similar size of penumbra (VT: 11±5% versus no VT: 11±4% of the total left ventricular mass, p=0.92). However, the total enhanced area was significantly smaller in patients with VTs as compared to patients without VTs (VT: 27±12% versus no VT: 32±11% of the total left ventricular mass, p=0.04). Consequently, small infarcts consisted of proportionally larger areas of penumbra (VT: 45±11% versus no VT: 38±11% of the total enhanced area, p=0.002). With decrease in total enhanced area size, the proportional amount of penumbra within the enhanced area increases (Pearson’s correlation -0.44, p<0.001). After correcting for the influence of the total enhanced area size, patients with proportionally more penumbra had more often VTs (Odds Ratio [OR] 1.05, 95% confidence interval 1.01-1.10, p=0.02). The infarct parameters in patients with and without VTs are described in table 1.
Univariate analysis showed a significant association between the occurrence of VTs and an episode of VF before revascularization, smaller size of the total enhanced area,
the presence of MVO, and a larger proportion of penumbra within the enhanced area (table 1). Multivariate logistic regression analysis identified the presence of VF before revascularization (OR 5.60, 95% confidence interval 1.54-20.30, p=0.009) and the percentage of penumbra within the total enhanced area (OR 1.06, 95% confidence interval 1.02-1.10, p=0.04) as independent predictors of the occurrence of VTs (table 2). The presence of MVO was inversely correlated with the occurrence of VTs on Holter (OR 0.41 [95% CI: 0.18-0.93], p=0.03). Myocardial infarcts that contained MVO were significantly larger (MVO: 35±10%; no MVO: 24±9%. P<0.001) and consisted of less penumbra (MVO: 35±9%; no MVO 44±11%. P<0.001). By combining these 3 parameters (total size of the enhanced area, percentage penumbra within the enhanced area and MVO) in a multivariate logistic regression model, the presence of MVO had no additional value for the prediction of VTs (OR 0.67 [95% CI 0.26-1.74], p=0.41).
Relative prognostic importance of infarct parameters to predict VTs
To further elucidate the relative prognostic importance and the interrelationship of the different infarct parameters, multiple multivariate analyses were performed including different parameters (table 3). When the infarct parameters were included in separate logistic regression models together with the presence of VF before primary PCI, the predictive value of the models, as expressed by the Nagelkerke R2, was strongest for model
1 including percentage penumbra of total enhanced myocardium (R2=0.15) compared
to the models including presence of MVO or percentage enhanced myocardium of total LV mass (models 2 and 3). More importantly, the odds ratio of percentage penumbra of enhanced myocardium did not substantially change when presence of MVO and percentage enhanced myocardium of total LV mass were added to the model (model 4), the OR changed from 1.06 (95% CI 1.02-1.10) to 1.05 (95% CI 1.00-1.09). In fact, presence of MVO and percentage enhanced myocardium of total LV mass were no longer associated with the occurrence of VT after adjusting. Thus, these findings suggest that the percentage penumbra of enhanced myocardium is the strongest and most important infarct parameter in relation to the occurrence of VT.
Penumbra and VTs in patients with an LVEF<40%
In patients with an LVEF<40% (n=59), 11 patients (19%) showed a VT on Holter recording. In patients with an LVEF≥40% (n=103), 18 patients (18%) showed a VT. The incidence of VTs did not differ significantly between the two subgroups (p=0.84). There was no interaction between LVEF and percentage penumbra of total enhanced myocardium with regard to the occurrence of VT. In the subgroup of patients with a LVEF of <40% the OR for percentage penumbra of total enhanced myocardium was 1.07 (95% CI 1.01-1.13) compared to 1.06 (95% CI 1.01 – 1.11) in the patients with LVEF ≥40% (p-value for interaction 0.84).
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Table 2. Univariate and multivariate logistic regression of parameters on the association with
ventricular tachycardias on Holter monitoring at 1 month follow-up (forward stepwise regression, inclusion of p<0.10).
Parameter Univariate analysis Multivariate analysis forward
OR 95% CI p-value OR 95% CI p-value
Age (year) 1.01 0.97-1.05 0.74
Male gender 0.66 0.22-1.96 0.45
Time between onset symptoms and primary
PCI (hours) 1.01 0.85-1.20 0.90
Presence of ventricular fibrillation before
primary PCI 5.48 1.62-18.48 0.01 5.60 1.54-20.29 0.01
LAD* related infarction 0.65 0.29-1.47 0.30
LV† indexed end-diastolic volume (ml/m2) 1.02 0.99-1.04 0.23 LV† indexed end-systolic volume (ml/m2) 1.01 0.99-1.04 0.34
LV† indexed stroke volume (ml/m2) 1.01 0.96-1.07 0.59
LV† ejection fraction (%) 0.99 0.94-1.04 0.65
QRS width (ms) 1.01 0.98-1.04 0.64
Corrected QT interval (ms) 0.99 0.98-1.01 0.43
Percentage enhanced myocardium of total LV†
mass 0.96 0.92-1.00 0.04
Presence of MVO 0.41 0.18-0.93 0.03
Percentage Penumbra of total LV† mass 1.00 0.90-1.10 0.92
Percentage Penumbra of total enhanced
myocardium 1.06 1.02-1.10 0.003 1.06 1.02-1.10 0.004
LAD=left anterior descending artery; LV=left ventricle; PCI=percutaneous coronary intervention; MVO= microvascular obstruction.
Table 3. Analysis of the relative prognostic importance of multiple infarct parameters for
predicting ventricular tachycardias on Holter monitoring at 1 month follow-up.
Parameter Multivariate analysis (enter)
OR 95% CI p-value R2
Model 1 0.15
Presence of VF* before primary PCI 5.60 1.55 - 20.3 0.009
Percentage Penumbra of total enhanced myocardium 1.06 1.02 - 1.10 0.004
Model 2 0.11
Presence of VF* before primary PCI 5.87 1.68 - 20.5 0.006
Presence of MVO 0.40 0.17 - 0.93 0.03
Model 3 0.11
Presence of VF* before primary PCI 5.71 1.64 - 19.9 0.006
Percentage enhanced myocardium of total LVmass 0.96 0.92 - 1.00 0.04
Model 4 0.17
Presence of VF* before primary PCI 5.81 1.56 - 21.6 0.009
Percentage Penumbra of total enhanced myocardium 1.05 1.00 - 1.09 0.05
Presence of MVO 0.65 0.24 - 1.75 0.39
Percentage Enhanced myocardium of total LV mass 0.99 0.94 - 1.04 0.69
VF=ventricular fibrillation; LV=left ventricle; PCI=percutaneous coronary intervention; MVO= microvascular obstruction.
DISCUSSION
This study focuses on the association and prognostic value of characterizing different regions within the myocardial infarction with LGE CMR imaging and the development of VTs early after AMI. Patients with myocardial enhancement consisting of larger proportions of penumbra showed more often ventricular arrhythmias at 1 month. Moreover, we found that the prevalence of VF before primary PCI is independently associated with the development of ventricular arrhythmias at 1 month.
Cell therapy and arrhythmogenesis
Among the 163 participating patients, no association was found between cell therapy treatment and the prevalence of VTs. However, one should consider that our study is not sufficiently powered to formally answer this question. Increased incidence of arrhythmias after cell therapy has been described in the past, but most of these studies were performed with other cell types than mononuclear cells (i.e. skeletal myoblasts). Also, the delivery method differed (e.g. intramyocardial injection as opposed to intracoronary infusion).10,11,20.
Early risk stratification for ventricular arrhythmias
Patients that suffered from VF before primary PCI were at increased risk for developing VTs at 1 month. This supports the theory that not only the ischemic processes due to the coronary occlusion contribute to ventricular arrhythmias, but that other factors (e.g. genetic predisposition and epigenetic phenomena) may facilitate the development of VF in the presence of ischemia.21 Theoretically, these additional factors may facilitate the
development of VF during scar tissue formation as well.
As stated before, the number of ICD-patients with a reduced ejection fraction after a prior myocardial infarction that receives appropriate shock therapy is low,6 while a substantial
proportion of these patients receives inappropriate ICD therapy.22 Although it is known
that premature prophylactic ICD therapy (i.e. the first 40 days after myocardial infarction) does not reduce overall mortality,23 early identification of patients at increased risk of
ventricular arrhythmias may assist in determining whether the patient may benefit from prophylactic ICD therapy at a later stage.
The penumbra and ventricular arrhythmias
To the best of our knowledge, this is the first study to show that early after revascularization of an AMI, the proportion of penumbra within the enhanced myocardium is already associated with increased incidence of VTs on Holter monitoring at 1 month. In this penumbra surrounding the infarcted myocardium, strands of healthy and damaged myocytes are interwoven. Hence, this area incorporates the necessary characteristics
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for arrhythmogenesis (i.e. a unidirectional pathway, short refractory period and decreased impulse conduction velocity).9-11 Additionally, the repair process itself may
also facilitate the arrhythmogenesis, as myofibroblasts infiltrate the infarcted area during scar tissue formation. These myofibroblasts can induce ectopic activity and facilitate arrhythmogenesis, in addition to the aforementioned characteristics.24,25 A recent rabbit
study showed that the intermediate density of myofibroblasts in the penumbra increases arrhythmia susceptibility, whereas a high density of myofibroblasts (as found in the infarct core) does not.26 Visualization of the extent of arrhythmogenic tissue with
LGE-CMR could become a valuable tool to assess the susceptibility for VTs in a safe and non-invasive manner.
CMR and ventricular arrhythmias in the subacute phase after AMI
LGE-CMR has already been proven to be an accurate and reproducible tool for measuring the total infarct size.13,27,28 Studies in chronic ischemic heart disease already
showed that infarct heterogeneity -by discriminating between different zones within the late gadolinium enhanced area- is associated with increased ventricular arrhythmias and mortality.29-31 Although the odds ratio of 1.06 may seem low at first, this corresponds to
an odds increase of 6% for VT development for each percentage increase in penumbra. Interestingly enough, MVO was inversely correlated with the occurrence of VTs on Holter. This is most likely caused by the fact that myocardial infarctions that contain MVO are generally larger and contain less arrhythmogenic penumbra around the infarct. Unfortunately, our study population is too small to further assess whether MVO has prognostic value for more severe arrhythmogenic events (sustained VTs, VF, sudden cardiac death).
This study was performed early after AMI, as opposed to the aforementioned studies in chronic myocardial infarction. Based on the general consensus for infarct size calculation, we used the threshold of 50% of the maximal SI of the infarcted area to discriminate between infarct core and surrounding penumbra.18 Unfortunately, almost no data exists on
the pathological justification or validation of any threshold for visualizing the penumbra in acute myocardial infarction. Additionally, no consensus has yet been reached in chronic myocardial infarction. A few studies assessed the penumbra –or border zone- in a chronic myocardial infarction.29-32 Yan et al.30 were the first to report a relationship
between the infarct ‘gray zone’ and mortality, using a signal intensity threshold between 2SD and 3SD from normal myocardium. Schmidt et al.29 and Heidary et al.,32 however,
defined the border zone as all myocardium with a SI above the maximum SI in the unaffected myocardium (up to 50% of the maximal SI in the infarcted area). Roes et al.31
used a slightly different definition for the border zone, with a signal intensity between 35% and 50% of the maximal SI of the infarcted area. In summary, most of these studies
performed in chronic MI chose a lower threshold around half of the range between the threshold of the infarct core area, and the remote, unaffected myocardium. We chose our threshold of 25%; this threshold correlated best with our visual evaluation of the penumbral area as well.
Myocardial tissue characteristics are markedly different in the subacute and chronic phase.33 In the first 5 days, myocardial tissue shows infiltration of leukocytes, migration of
myofibroblasts towards the infarcted area, interstitial oedema, myocardial haemorrhage and necrotic myocytes. In the chronic phase, cellular debris has been cleared, collagen fibrils are deposited and a fibrous scar tissue is formed.33 Although the histological content
of the penumbra surrounding the infarcted core area is markedly different in subacute and chronic myocardial infarction, this study shows that the ‘subacute phase’-penumbra already has predictive value for VTs. However, the differences in tissue composition between acute and chronic myocardial infarction give rise to different pharmacodynamic properties of Gadolinium, making an exact comparison for the enhanced area size and the proportion of core and penumbra, difficult.28,34,35.
Limitations
Although the surrounding of intermediate signal intensity that we call the penumbra shows an association with VTs, one should consider that LGE-CMR at 1.5 T does not show the myocardial tissue at the cellular level. This creates an averaging of the signal for all tissues in each voxel, called partial volume averaging. Owing to this partial volume averaging, no distinction can be made between tissue consisting of disorganized mixtures of damaged and viable myocytes, and a border where a sharply demarcated infarction meets unaffected tissue within one voxel. Additionally, the definition for ‘infarct penumbra’ as used in our study still lacks pathological validation; the exact histological correlate of the penumbra in the subacute phase of AMI should be an area for future studies to explore.
CONClUSION
Early after myocardial infarction, the proportional amount of penumbra within the gadolinium-enhanced area is already associated with an increased risk of developing VTs, supporting the theory that the heterogeneous penumbral tissue may be pro-arrhythmogenic. Thus, non-invasive assessment of infarct tissue characteristics by CMR may assist in identifying patients at risk of developing VTs and improve risk stratification for prophylactic ICD therapy after acute myocardial infarction.
6
Acknowledgements
We would like to thank the investigators and coordinators of the participating institutions for their assistance in the data acquisition and most of all the patients that participated in the trial.
The HEBE main trial was financially supported by funds provided by the ICIN – Netherlands Heart Institute, Utrecht, the Netherlands; the Netherlands Heart Foundation (2005T101); and by unrestricted grants from Biotronik, Boston Scientific, Guerbet, Guidant, Medtronic, Novartis, Pfizer, and Sanofi-Aventis. This work was supported by a grant from the Dutch Heart Foundation and National Health Insurance Board/ZON MW, the Netherlands to R.D. Grant number 2011T022 + 40-00703-98-11629.
REFERENCES
1. Henkel DM, Witt BJ, Gersh BJ, Jacobsen SJ, Weston SA, Meverden RA, Roger VL. Ventricular arrhythmias after acute myocardial infarction: a 20-year community study. Am
Heart J 2006; 151(4): 806-812
2. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo AL, Wilber D, Brown MW, Heo M. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996; 335(26): 1933-1940
3. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346(12): 877-883 4. Scirica BM, Braunwald E, Belardinelli L, Hedgepeth CM, Spinar J, Wang W, Qin J,
Karwatowska-Prokopczuk E, Verheugt FW, Morrow DA. Relationship between nonsustained ventricular tachycardia after non-ST-elevation acute coronary syndrome and sudden cardiac death: observations from the metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndrome-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2010; 122(5): 455-462
5. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352(3): 225-237
6. Moss AJ, Greenberg H, Case RB, Zareba W, Hall WJ, Brown MW, Daubert JP, McNitt S, Andrews ML, Elkin AD. Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator. Circulation 2004; 110(25): 3760-3765
7. Coumel P. The management of clinical arrhythmias. An overview on invasive versus non-invasive electrophysiology. Eur Heart J 1987; 8(2): 92-99
8. Klem I, Weinsaft JW, Bahnson TD, Hegland D, Kim HW, Hayes B, Parker MA, Judd RM, Kim RJ. Assessment of myocardial scarring improves risk stratification in patients evaluated for cardiac defibrillator implantation. J Am Coll Cardiol 2012; 60(5): 408-420
9. Stevenson WG, Weiss JN, Wiener I, Nademanee K. Slow conduction in the infarct scar: relevance to the occurrence, detection, and ablation of ventricular reentry circuits resulting from myocardial infarction. Am Heart J 1989; 117(2): 452-467
10. Breithardt G, Borggrefe M, Martinez-Rubio A, Budde T. Pathophysiological mechanisms of ventricular tachyarrhythmias. Eur Heart J 1989; 10 Suppl E: 9-18
11. Castellanos A, Jr., Lemberg L, Arcebal AG. Mechanisms of slow ventricular tachycardias in acute myocardial infarction. Dis Chest 1969; 56(6): 470-476
6
12. Goldman MR, Brady TJ, Pykett IL, Burt CT, Buonanno FS, Kistler JP, Newhouse JH, Hinshaw WS, Pohost GM. Quantification of experimental myocardial infarction using nuclear magnetic resonance imaging and paramagnetic ion contrast enhancement in excised canine hearts. Circulation 1982; 66(5): 1012-1016
13. Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, Bundy J, Finn JP, Klocke FJ, Judd RM. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999; 100(19): 1992-2002
14. Hirsch A, Nijveldt R, van der Vleuten PA, Biemond BJ, Doevendans PA, van Rossum AC, Tijssen JG, Zijlstra F, Piek JJ. Intracoronary infusion of autologous mononuclear bone marrow cells or peripheral mononuclear blood cells after primary percutaneous coronary intervention: Rationale and design of the HEBE trial--A prospective, multicenter, randomized trial. Am Heart J 2006; 152(3): 434-441
15. Hirsch A, Nijveldt R, van der Vleuten PA, Tijssen JG, van der Giessen WJ, Tio RA, Waltenberger J, Ten Berg JM, Doevendans PA, Aengevaeren WR, Zwaginga JJ, Biemond BJ, van Rossum AC, Piek JJ, Zijlstra F. Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial. Eur Heart J 2011; 32(14): 1736-1747
16. Robbers LF, Nijveldt R, Beek AM, Kemme MJ, Delewi R, Hirsch A, van der Laan AM, van der Vleuten PA, Piek JJ, Zijlstra F, van Rossum AC. Intracoronary infusion of mononuclear cells after PCI-treated myocardial infarction and arrhythmogenesis: is it safe? Neth Heart J 2012; 20(3): 133-137
17. Beek AM, Bondarenko O, Afsharzada F, van Rossum AC. Quantification of late gadolinium enhanced CMR in viability assessment in chronic ischemic heart disease: a comparison to functional outcome. J Cardiovasc Magn Reson 2009; 11: 6
18. Flett AS, Hasleton J, Cook C, Hausenloy D, Quarta G, Ariti C, Muthurangu V, Moon JC. Evaluation of techniques for the quantification of myocardial scar of differing etiology using cardiac magnetic resonance. JACC Cardiovasc Imaging 2011; 4(2): 150-156
19. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC, Jr., Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006; 48(5): e247-e346
20. Smith RR, Barile L, Messina E, Marban E. Stem cells in the heart: what’s the buzz all about? Part 2: Arrhythmic risks and clinical studies. Heart Rhythm 2008; 5(6): 880-887
21. Dekker LR, Bezzina CR, Henriques JP, Tanck MW, Koch KT, Alings MW, Arnold AE, de Boer MJ, Gorgels AP, Michels HR, Verkerk A, Verheugt FW, Zijlstra F, Wilde AA. Familial sudden death is an important risk factor for primary ventricular fibrillation: a case-control study in acute myocardial infarction patients. Circulation 2006; 114(11): 1140-1145
22. Daubert JP, Zareba W, Cannom DS, McNitt S, Rosero SZ, Wang P, Schuger C, Steinberg JS, Higgins SL, Wilber DJ, Klein H, Andrews ML, Hall WJ, Moss AJ. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol 2008; 51(14): 1357-1365
23. Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R, Fain E, Gent M, Connolly SJ. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med 2004; 351(24): 2481-2488
24. Miragoli M, Salvarani N, Rohr S. Myofibroblasts induce ectopic activity in cardiac tissue.
Circ Res 2007; 101(8): 755-758
25. Rohr S. Myofibroblasts in diseased hearts: new players in cardiac arrhythmias? Heart Rhythm 2009; 6(6): 848-856
26. McDowell KS, Arevalo HJ, Maleckar MM, Trayanova NA. Susceptibility to arrhythmia in the infarcted heart depends on myofibroblast density. Biophys J 2011; 101(6): 1307-1315 27. Kim HW, Farzaneh-Far A, Kim RJ. Cardiovascular magnetic resonance in patients with
myocardial infarction: current and emerging applications. J Am Coll Cardiol 2009; 55(1): 1-16 28. Kim RJ, Chen EL, Lima JA, Judd RM. Myocardial Gd-DTPA kinetics determine MRI
contrast enhancement and reflect the extent and severity of myocardial injury after acute reperfused infarction. Circulation 1996; 94(12): 3318-3326
29. Schmidt A, Azevedo CF, Cheng A, Gupta SN, Bluemke DA, Foo TK, Gerstenblith G, Weiss RG, Marban E, Tomaselli GF, Lima JA, Wu KC. Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction. Circulation 2007; 115(15): 2006-2014
30. Yan AT, Shayne AJ, Brown KA, Gupta SN, Chan CW, Luu TM, Di Carli MF, Reynolds HG, Stevenson WG, Kwong RY. Characterization of the peri-infarct zone by contrast-enhanced cardiac magnetic resonance imaging is a powerful predictor of post-myocardial infarction mortality. Circulation 2006; 114(1): 32-39
31. Roes SD, Borleffs CJ, van der Geest RJ, Westenberg JJ, Marsan NA, Kaandorp TA, Reiber JH, Zeppenfeld K, Lamb HJ, de RA, Schalij MJ, Bax JJ. Infarct tissue heterogeneity assessed with contrast-enhanced MRI predicts spontaneous ventricular arrhythmia in patients with ischemic cardiomyopathy and implantable cardioverter-defibrillator. Circ Cardiovasc Imaging 2009; 2(3): 183-190
32. Heidary S, Patel H, Chung J, Yokota H, Gupta SN, Bennett MV, Katikireddy C, Nguyen P, Pauly JM, Terashima M, McConnell MV, Yang PC. Quantitative tissue characterization of infarct core and border zone in patients with ischemic cardiomyopathy by magnetic
6
resonance is associated with future cardiovascular events. J Am Coll Cardiol 2010; 55(24): 2762-2768
33. Saffitz JE. The Heart; Ischemic Heart Disease. In: Rubin E, Gorstein F, Rubin R, Schwarting R, Strayer D, eds. Rubin’s Pathology; Clinicopathologic Foundations of Medicine. 4th Edition ed. Baltimore, Maryland: Lippincott Williams & Wilkins; 2005. p. 541-552.
34. Klein C, Nekolla SG, Balbach T, Schnackenburg B, Nagel E, Fleck E, Schwaiger M. The influence of myocardial blood flow and volume of distribution on late Gd-DTPA kinetics in ischemic heart failure. J Magn Reson Imaging 2004; 20(4): 588-593
35. Klein C, Schmal TR, Nekolla SG, Schnackenburg B, Fleck E, Nagel E. Mechanism of late gadolinium enhancement in patients with acute myocardial infarction. J Cardiovasc Magn
Appendix 1.
Cardiac magnetic resonance imaging and ar
rh
ythmia characteristics stratified by different treatment g
roups . T otal g roup (n=162) BMMC (n=60) PBM (n=53) Control (n=49) BMMC vs. Control PBMC vs. Control Da ys betw een primar
y PCI and MRI
3 (3-4) 3 (2-4) 3 (3-4) 3 (3-5) 0.79 0.81
Functional and infarct mass parameters LV
† inde xed end-diastolic v olume (ml•m-2) 98 ± 16 97 ± 14 98 ± 16 100 ± 17 0.39 0.50 LV † inde xed end-systolic v olume (ml•m-2) 57 ± 15 55 ± 15 57 ± 15 59 ± 15 0.20 0.37 LV † inde xed stroke v olume (ml•m-2) 41 ± 8 42 ± 8 41 ± 8 41 ± 9 0.45 0.76 LV † ejection fraction (%) 43 ± 9 44 ± 9 43 ± 8 41 ± 8 0.14 0.37 P ercentag e Enhanced m yocardium of total L V mass (%) 31% ± 11% 30% ± 11% 29% ± 11% 33% ± 12% 0.12 0.08 P ercentag e Core zone of total L V mass (%) 19% ± 9% 18% ± 9% 19% ± 9% 21% ± 10% 0.09 0.17 P ercentag e Core zone of total enhanced m yocardium (%) 61% ± 11% 59% ± 12% 63% ± 11% 62% ± 10% 0.20 0.63 P ercentag e P en umbra of total L V mass (%) 11% ± 4% 12% ± 4% 11% ± 4% 12% ± 4% 0.57 0.05 P ercentag e P en umbra of total enhanced m yocardium (%) 39% ± 11% 41% ± 12% 37% ± 11% 38% ± 10% 0.21 0.60 Core/P en umbra ratio 1.8 ± 0.9 1.7 ± 0.9 2.0 ± 1.1 1.8 ± 0.8 0.43 0.41 Ar rh ythmia parameters QRS duration (ms) at 1 month 94 (86-100) 92 (83-100) 94 (87-100) 96 (89-101) 0.08 0.08 Cor rected QT inter val (QT c) at 1 month 420 ± 28 418 ± 29 418 ± 28 423 ± 25 0.37 0.33 Ser um sodium le
vel (mMol•l-1) at 1 month
141 ± 2 141 ± 2 141 ± 2 142 ± 2 0.53 0.02 Ser um potassium le
vel (mMol•l-1) at 1 month
4.3 ± 0.3 4.4 ± 0.4 4.3 ± 0.3 4.3 ± 0.3 0.65 0.75
Beta-blocker use during Holter monitoring (%)
152 94% 55 92% 49 93% 48 98% 0.22 a 0.36 a P ercentag
e patients with triplet PV
Cs(%) 27 17% 9 15% 10 19% 8 16% 0.85 0.74 P ercentag e patients with VT s(≥4 PV Cs) (%) 29 18% 9 15% 11 21% 9 18% 0.64 0.76 P ercentag
e patients with both triplet PV
Cs and VT s(%) 13 8% 4 7% 6 11% 3 6% 1.00 a 0.49 a No . of triplet PV
Cs 24 hours (when present)
1.0 (1.0-3.0) 2.0 (1.0-4.0) 1.0 (1.0-1.0) 1.5 (1.0-3.0) 0.74 0.42 No . of VT s(when present) 1.0 (1.0-3.0) 1.0 (1.0-2.5) 2.0 (1.0-3.0) 1.0 (1.0-3.0) 0.69 0.73 Shor test RR inter val of triplet PV Cs (ms) 420 (375-490) 440 (345-528) 460 (365-495) 410 (390-430) 0.29 0.22 Shor test RR inter val of VTs (ms) 400 (370-465) 410 (345-483) 400 (370-500) 380 (370-440) 0.75 0.65 BMMC=bone mar ro w-deri ved monon uclear cells; PBMC=peripheral blood-deri ved monon uclear cells; LV=left ventricle; MRI=magn etic resonance
imaging; PCI=percutaneous coronar
y inter vention; PV C=premature v entricular comple x; VT=v entricular tach ycardia.
Data are presented as mean+SD
, median (IQR) or total n
umber (percentag
e). *Fisher’
s e
