Pieter A. van der Vleuten

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

AIMSnPrevious trials that investigated cell therapy as an adjunctive therapy after acute myocardial infarction (AMI) have shown conflicting results. We designed a randomized controlled trial to determine the effect of intracoronary infusion of mononuclear cells from bone marrow (BM) or peripheral blood in patients with AMI.nnnMETHODS AND RESULTSnIn a multicentre trial, 200 patients with large first AMI treated with primary percutaneous coronary intervention were randomly assigned to either intracoronary infusion of mononuclear BM cells (n = 69), mononuclear peripheral blood cells (n = 66), or standard therapy (without placebo infusion) (n = 65). Mononuclear cells were delivered intracoronary between 3 and 8 days after AMI. Regional and global left ventricular myocardial function and volumes were assessed by magnetic resonance imaging before randomization and at 4 months, and clinical events were reported. The primary endpoint of the percentage of dysfunctional left ventricular segments that improved during follow-up did not differ significantly between either of the treatment groups and control: 38.6 ± 24.7% in the BM group, 36.8 ± 20.9% in the peripheral blood group, and 42.4 ± 18.7% in the control group (P = 0.33 and P = 0.14). Improvement of left ventricular ejection fraction was 3.8 ± 7.4% in the BM group, 4.2 ± 6.2% in the peripheral blood group when compared with 4.0 ± 5.8% in the control group (P = 0.94 and P = 0.90). Furthermore, the three groups did not differ significantly in changes in left ventricular volumes, mass, and infarct size and had similar rates of clinical events.nnnCONCLUSIONnIntracoronary infusion of mononuclear cells from BM or peripheral blood following AMI does not improve regional or global systolic myocardial function in the HEBE trial.nnnREGISTRATIONnThe Netherlands Trial Register #NTR166 (www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (http://isrctn.org).

A proinflammatory monocyte response is associated with myocardial injury and impaired functional outcome in patients with ST-segment elevation myocardial infarction: Monocytes and myocardial infarction

BACKGROUNDnIn patients with ST-segment elevation myocardial infarction (STEMI), the importance of a well-balanced inflammatory reaction has been recognized for years. Monocytes play essential roles in regulating inflammation. Hence, we investigated the association between inflammatory characteristics of monocytes and myocardial injury and functional outcome in patients with STEMI.nnnMETHODSnUsing flow cytometry, the levels of classical (CD14(++)CD62L(+)) and nonclassical (CD14(+)CD62L(-)) monocytes were analyzed in peripheral blood in 58 patients with STEMI at a median of 5 days (4-6 days) after primary percutaneous coronary intervention. In addition, the monocytic expression of several surface molecules and formation of monocyte-platelet complexes were measured. All patients underwent cardiovascular magnetic resonance imaging at baseline and 4-month follow-up.nnnRESULTSnAt baseline, patients with high levels of classical monocytes had impaired left ventricular (LV) ejection fraction (P = .002), larger infarct size (P = .001), and, often, presence of microvascular obstruction (P = .003). At follow-up, high levels of classical monocytes were negatively associated with the regional systolic LV function independent of the transmural extent of infarction. In contrast, positive associations for the levels of nonclassical monocytes were observed. Finally, up-regulation of macrophage 1 by blood monocytes and increased formation of monocyte-platelet complexes were associated with enhanced myocardial injury at baseline and impaired LV function at follow-up.nnnCONCLUSIONSnThis study shows an association between a proinflammatory monocyte response, characterized by high levels of classical monocytes, and severe myocardial injury and poor functional outcome after STEMI. Future studies are required to investigate the biologic nature of this association and therapeutic implications.

Intracoronary infusion of autologous mononuclear bone marrow cells in patients with acute myocardial infarction treated with primary PCI: Pilot study of the multicenter HEBE trial

Objective: This study was a pilot trial to determine safety and feasibility of intracoronary infusion of mononuclear bone marrow cells (MBMC) in patients with acute myocardial infarction (MI). Background: Studies reporting the effect of MBMC therapy on improvement of left ventricular (LV) function have shown variable results. The HEBE trial is a large multicenter, randomized trial that currently enrolls patients. Prior to this trial we performed a pilot study. Methods: Twenty‐six patients with a first acute MI were prospectively enrolled in eight centers. Bone marrow aspiration was performed at a median of 6 days after primary PCI (interquartile range, 5–7 days). MBMC were isolated by gradient centrifugation and were infused intracoronary the same day. All patients underwent magnetic resonance imaging before cell infusion and after 4 months. Clinical events were assessed up to 12 months. Results: Within 10 hr after bone marrow aspiration, 246 ± 133 × 106 MBMC were infused, of which 3.9 ± 2.3 × 106 cells were CD34+. In one patient, this procedure was complicated by local dissection. LV ejection fraction significantly increased from 45.0 ± 6.3% to 47.2 ± 6.5% (P = 0.03). Systolic wall thickening in dysfunctional segments at baseline improved with 0.9 ± 0.7 mm (P < 0.001). Infarct size decreased 37% from 17.8 ± 8.2 to 11.2 ± 4.2 gram (P < 0.001). During 12‐month follow‐up, 3 additional revascularizations were performed and an ICD was implanted in one patient, 3 weeks after PCI. Conclusion: In patients with acute MI, intracoronary infusion of MBMC is safe in a multicenter setting. At 4‐month follow‐up, a modest increase in global and regional LV function was observed, with a concomitant decrease in infarct size.

Evaluation of global left ventricular function assessment by dual-source computed tomography compared with MRI

Left ventricular (LV) function assessment by dual-source computed tomography (DSCT) was compared with the reference standard method using magnetic resonance imaging (MRI). Accurate assessment of LV function is essential for the prediction of prognosis in cardiac disease. Thirty-four patients undergoing DSCT examination of the heart for various clinical indications underwent MRI after DSCT. Short-axis cine images were reconstructed from the DSCT datasets and were analyzed using a dedicated post-processing software-tool to generate global left ventricular function parameters. Five DSCT datasets were considered to be of insufficient image quality. DSCT showed a small overestimation of end-diastolic and end-systolic volumes of 11.0xa0ml and 3.5xa0ml, nrespectively. Myocardial mass assessed by DSCT showed an average underestimation of 0.2xa0g. DSCT showed a small overestimation of LV ejection fraction (LVEF) of 0.4%-point with a Bland-Altman interval of [−8.67 (0.40) 9.48]. Global LV functional parameters calculated from DSCT datasets acquired in daily clinical practice correlated well with MRI and may be considered interchangeable. However, visual assessment of the image quality of the short-axis cine slices should be performed to detect any artifacts in the DSCT data which could influence accuracy.

Early Electrocardiographic Findings and MR Imaging-Verified Microvascular Injury and Myocardial Infarct Size

OBJECTIVESnThis study investigated early electrocardiographic findings in relation to left ventricular (LV) function, extent and size of infarction, and microvascular injury in patients with acute myocardial infarction (MI) treated with percutaneous coronary intervention (PCI).nnnBACKGROUNDnThe electrocardiogram (ECG) is the most used and simplest clinical method to evaluate the risk for patients immediately after reperfusion therapy for acute MI. ST-segment resolution and residual ST-segment elevation have been used for prognosis in acute MI, whereas Q waves are related to outcome in chronic MI. We hypothesized that the combination of these electrocardiographic measures early after primary PCI would enhance risk stratification.nnnMETHODSnWe prospectively included 180 patients with a first acute ST-segment elevation MI to assess ST-segment resolution, residual ST-segment elevation, and number of Q waves using the 12-lead ECG acquired on admission and 1 h after successful PCI. The ECG findings were related to LV function, infarction size and transmurality, and microvascular injury as assessed with cine and gadolinium-enhanced cardiac magnetic resonance 4 +/- 2 days after reperfusion therapy.nnnRESULTSnResidual ST-segment elevation (beta = -2.00, p = 0.004) and the number of Q waves (beta = -1.66, p = 0.005) were independent ECG predictors of LV ejection fraction. Although the number of Q waves was the only independent predictor of infarct size (beta = 2.01, p < 0.001) and transmural extent of infarction (beta = 0.60, p < 0.001), residual ST-segment elevation was the only independent predictor of microvascular injury (odds ratio: 19.1, 95% confidence interval: 2.4 to 154, p = 0.005) in multivariable analyses. The ST-segment resolution was neither associated with LV function, infarct size, or transmurality indexes, nor with microvascular injury in multivariable analysis.nnnCONCLUSIONSnIn patients after successful coronary intervention for acute MI, residual ST-segment elevation and the number of Q waves on the post-procedural ECG offer valuable complementary information on prediction of myocardial function and necrosis and its microvascular status.

The importance of left ventricular function for long-term outcome after primary percutaneous coronary intervention

BackgroundIn the present study we sought to determine the long-term prognostic value of left ventricular ejection fraction (LVEF), assessed by planar radionuclide ventriculography (PRV), after ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PPCI).MethodsIn total 925 patients underwent PRV for LVEF assessment after PPCI for myocardial infarction before discharge from the hospital. PRV was performed with a standard dose of 500 Mbq of 99mTc-pertechnetate. Average follow-up time was 2.5 years.ResultsMean (± SD) age was 60 ± 12 years. Mean (± SD) LVEF was 45.7 ± 12.2 %. 1 year survival was 97.3 % and 3 year survival was 94.2 %. Killip class, multi vessel-disease, previous cardiovascular events, peak creatin kinase and its MB fraction, age and LVEF proved to be univariate predictors of mortality. When entered in a forward conditional Cox regression model age and LVEF were independent predictors of 1 and 3 year mortality.ConclusionLVEF assessed by PRV is a powerful independent predictor of long term mortality after PPCI for STEMI.

Myocardial infarct heterogeneity assessment by late gadolinium enhancement cardiovascular magnetic resonance imaging shows predictive value for ventricular arrhythmia development after acute myocardial infarction

AIMSnThe 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).nnnMETHODSnOne-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.nnnRESULTSnThe 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.nnnCONCLUSIONnLarger 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.

Pathological Q Waves in Myocardial Infarction in Patients Treated by Primary PCI

OBJECTIVESnIn the present study, we investigated the association of pathological Q waves with infarct size. Furthermore, we investigated whether Q-wave regression was associated with improvement of left ventricular ejection fraction (LVEF), infarct size, and left ventricular dimensions in ST-segment elevation myocardial infarction (STEMI) patients with early Q-wave formation compared with patients without or persistent pathological Q waves.nnnBACKGROUNDnThe criteria for pathological Q waves after acute myocardial infarction (MI) have changed over the years. Also, there are limited data regarding correlation of Q-wave regression and preservation of LVEF in patients with an initial Q-wave MI.nnnMETHODSnStandard 12-lead electrocardiograms (ECGs) were recorded in 184 STEMI patients treated with primary percutaneous coronary intervention (PCI). ECGs were recorded before and following PCI, as well as at 1, 4, 12, and 24 months of follow-up. An ECG was scored as Q-wave MI when it showed Q waves in 2 or more contiguous leads according to the 4 readily available clinical definitions used over the years: classic criteria, Thrombolysis In Myocardial Infarction criteria, and 2000 and 2007 consensus criteria. Cardiac magnetic resonance (CMR) examination was performed at 4 ± 2 days after reperfusion and repeated after 4 and 24 months. Contrast-enhanced CMR was performed at baseline and 4 months.nnnRESULTSnThe classic ECG criteria showed strongest correlation with infarct size as measured by CMR. The incidence of Q-wave MI according to the classic criteria was 23% 1 h after PCI. At 24 months of follow-up, 40% of patients with initial Q-wave MI displayed Q-wave regression. Patients with a Q-wave MI had larger infarct size and lower LVEF on baseline CMR (24 ± 10% LV mass and 37 ± 8%, respectively) compared with patients with non-Q-wave MI (17 ± 9% LV mass, p < 0.01, and 45 ± 8%, p < 0.001, respectively). Patients with Q-wave regression displayed significantly larger LVEF improvement in 24 months (9 ± 11%) as compared with both persistent Q-wave MI (2 ± 8%) as well as non-Q-wave MI (3 ± 8%, p = 0.04 for both comparisons).nnnCONCLUSIONSnAssociation of Q waves with infarct size is strongest when using the classic Q-wave criteria. Q-wave regression is associated with the largest improvement of LVEF as assessed with CMR.

Predictive value of tissue Doppler imaging for left ventricular ejection fraction, remodelling, and infarct size after percutaneous coronary intervention for acute myocardial infarction

AIMSnTo investigate in ST-elevation myocardial infarction (STEMI) patients the value of tissue Doppler imaging (TDI) for an early estimation of the extent of myocardial salvage, left ventricular (LV) remodelling, and residual LV ejection fraction (LVEF).nnnMETHODS AND RESULTSnIn 50 STEMI patients hospitalized for primary percutaneous coronary intervention (PCI), we investigated whether TDI can predict LVEF, infarct size, and LV remodelling as measured by magnetic resonance imaging (MRI) at 4 months post-MI. TDI was assessed within 24 h after MI with colour-coded TDI. Systolic and diastolic velocities from the six basal myocardial segments derived from three standard apical windows were averaged as a measure of global longitudinal velocity (i.e. Sm-6 and Em-6/Am-6, respectively). Sm-6 was shown to be a significant predictor of LVEF at 4 months. In addition, Sm-6 was a significant predictor of infarct size. No significant correlations were found between Sm-6 and LV remodelling. In addition, Sm-6 appeared to be a valuable clinical tool for identification of patients with LVEF > 40% or LVEF < 40% with acceptable positive predictive values.nnnCONCLUSIONnSm-6 is a significant predictor of post-MI LVEF and infarct size as measured by MRI. In contrast, TDI-derived velocities do not predict LV remodelling.

Long term outcome after mononuclear bone marrow or peripheral blood cells infusion after myocardial infarction

Objectives This study reports the long-term follow-up of the randomised controlled HEBE trial. The HEBE study is a multicentre trial that randomised 200 patients with large first acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention to either intracoronary infusion of bone marrow mononuclear cells (BMMCs) (n=69), peripheral blood mononuclear cells (PBMCs) (n=66) or standard therapy (n=65). Methods In addition to 3–5u2005days, and 4u2005months after AMI, all patients underwent cardiac MRI after 2u2005years. A follow-up for 5u2005years after AMI was performed to assess clinical adverse events, including death, myocardial reinfarction and hospitalisation for heart failure. Results Of the 200 patients enrolled, 9 patients died and 12 patients were lost to follow-up at 5u2005years after AMI. BMMC group showed less increase in LV end-diastolic volume (LVEDV) (3.5±16.9u2005mL/m2) compared with (11.2±19.8u2005mL/m2, p=0.03) in the control group, with no difference between the PBMC group (9.2±20.9u2005mL/m2) and controls (p=0.69). Moreover, the BMMC group showed a trend for decrease in LV end systolic volume (−1.8±15.0u2005mL/m2) as compared with controls (3.0±16.3u2005mL/m2, p=0.07), with again no difference between PBMC (3.3±18.8u2005mL/m2) and controls (p=0.66). The combined endpoint of death and hospitalisation for heart failure was non-significantly less frequent in the BMMC group compared with the control group (n=4 vs n=1, p=0.20), with no difference between PBMC and controls (n=6 vs n=4, p=0.74). The composite endpoint of death or recurrent myocardial infarction was significantly higher in the PBMC group compared with controls (14 patients vs 3 patients, p=0.008), with no difference between the BMMC group and controls (2 vs 3 patients, p=0.67). Conclusions Long-term follow-up of the HEBE trial showed that increase in LVEDV was lower in the BMMC group. This study supports the long-term safety of intracoronary BMMC therapy. However, major clinical cardiovascular adverse events were significantly more frequent in the PBMC group. Trial registration number The Netherlands Trial Register #NTR166 (http://www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (http://isrctn.org).