Gerd Peter Meyer

Intracoronary Bone Marrow Cell Transfer After Myocardial Infarction Eighteen Months’ Follow-Up Data From the Randomized, Controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) Trial

Background— Intracoronary transfer of autologous bone marrow cells (BMCs) may enhance recovery of left ventricular (LV) function in patients after acute myocardial infarction (AMI). However, clinical studies addressing the effects of BMCs after AMI have covered only limited time frames ranging from 3 to 6 months. The critical question of whether BMC transfer can have a sustained impact on LV function remains unanswered. Methods and Results– After percutaneous coronary intervention with stent implantation (PCI) of the infarct-related artery, 60 patients were randomized 1:1 to a control group with optimal postinfarction therapy and a BMC transfer group that also received an intracoronary BMC infusion 4.8±1.3 days after PCI. Cardiac MRI was performed 3.5±1.5 days, 6±1 months, and 18±6 months after PCI. BMC transfer was not associated with adverse clinical events. In the control group, mean global LV ejection fraction increased by 0.7 and 3.1 percentage points after 6 and 18 months, respectively. LV ejection fraction in the BMC transfer group increased by 6.7 and 5.9 percentage points. The difference in LVEF improvement between groups was significant after 6 months but not after 18 months (P=0.27). The speed of LV ejection fraction recovery over the course of 18 months was significantly higher in the BMC transfer group (P=0.001). Conclusions– In this study, a single dose of intracoronary BMCs did not provide long-term benefit on LV systolic function after AMI compared with a randomized control group; however, the study suggests an acceleration of LV ejection fraction recovery after AMI by BMC therapy.

Monitoring of Bone Marrow Cell Homing Into the Infarcted Human Myocardium

Background—Intracoronary transfer of autologous bone marrow cells (BMCs) promotes recovery of left ventricular systolic function in patients with acute myocardial infarction. Although the mechanisms of this effect remain to be established, homing of BMCs into the infarcted myocardium is probably a critical early event. Methods and Results—We determined BMC biodistribution after therapeutic application in patients with a first ST-segment–elevation myocardial infarction who had undergone stenting of the infarct-related artery. Unselected BMCs were radiolabeled with 100 MBq 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) and infused into the infarct-related coronary artery (intracoronary; n=3 patients) or injected via an antecubital vein (intravenous; n=3 patients). In 3 additional patients, CD34-positive (CD34+) cells were immunomagnetically enriched from unselected BMCs, labeled with 18F-FDG, and infused intracoronarily. Cell transfer was performed 5 to 10 days after stenting. More than 99% of the infused total radioactivity was cell bound. Nucleated cell viability, comparable in all preparations, ranged from 92% to 96%. Fifty to 75 minutes after cell transfer, all patients underwent 3D PET imaging. After intracoronary transfer, 1.3% to 2.6% of 18F-FDG–labeled unselected BMCs were detected in the infarcted myocardium; the remaining activity was found primarily in liver and spleen. After intravenous transfer, only background activity was detected in the infarcted myocardium. After intracoronary transfer of 18F-FDG–labeled CD34-enriched cells, 14% to 39% of the total activity was detected in the infarcted myocardium. Unselected BMCs engrafted in the infarct center and border zone; homing of CD34-enriched cells was more pronounced in the border zone. Conclusions—18F-FDG labeling and 3D PET imaging can be used to monitor myocardial homing and biodistribution of BMCs after therapeutic application in patients.

Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial

AIMS We assessed whether a single intracoronary infusion of autologous bone marrow cells (BMCs) can have a sustained impact on left ventricular ejection fraction (LVEF) in patients after ST-elevation myocardial infarction (STEMI). In the BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) trial, 60 patients with STEMI and successful percutaneous coronary intervention were randomized to a control and a cell therapy group. As previously reported, BMC transfer led to an improvement of LVEF by 6.0% at 6 months (P = 0.003) and 2.8% at 18 months (P = 0.27). METHODS AND RESULTS Left ventricular ejection fraction and clinical status were re-assessed in all surviving patients after 61 +/- 11 months. Major adverse cardiac events occurred with similar frequency in both groups. When compared with baseline, LVEF assessed by magnetic resonance imaging at 61 months decreased by 3.3 +/- 9.5% in the control group and by 2.5 +/- 11.9% in the BMC group (P = 0.30). Patients with an infarct transmurality > median appeared to benefit from BMC transfer throughout the 61-month study period (P = 0.040). CONCLUSION A single intracoronary application of BMCs does not promote a sustained improvement of LVEF in STEMI patients with relatively preserved systolic function. It is conceivable that a subgroup of patients with more transmural infarcts may derive a sustained benefit from BMC therapy. However, this needs to be tested prospectively in a randomized trial.

Bone marrow cells are a rich source of growth factors and cytokines: implications for cell therapy trials after myocardial infarction

AIMS Results from clinical trials suggest that cardiac function after acute myocardial infarction (AMI) can be enhanced by an intracoronary infusion of autologous unselected nucleated bone marrow cells (BMCs). Release of paracrine factors has been proposed as a mechanism for these therapeutic effects; however, this hypothesis has not been tested in humans. METHODS AND RESULTS BMCs and peripheral blood leucocytes (PBLs) were obtained from 15 patients with AMI and cultured in serum-free medium to obtain conditioned supernatants (SN). BMC-SN stimulated human coronary artery endothelial cell proliferation, migration, and tube formation, and induced cell sprouting in a mouse aortic ring assay. Moreover, BMC-SN protected rat cardiomyocytes from cell death induced by simulated ischaemia or ischaemia followed by reperfusion. While PBL-SN promoted similar effects on endothelial cells and cardiomyocytes, BMC-SN and PBL-SN in combination promoted synergistic effects. As shown by ProteinChip and GeneChip array analyses (each performed in triplicate), BMCs and PBLs expressed distinct patterns of pro-angiogenic and cytoprotective secreted factors. CONCLUSION Our data support the paracrine hypothesis and suggest that characterization of the BMC secretome may lead to an identification of factors with therapeutic potential after AMI.

In vitro validation of phase-contrast flow measurements at 3 T in comparison to 1.5 T: Precision, accuracy, and signal-to-noise ratios†

To evaluate the signal‐to‐noise ratio (SNR), precision, and accuracy of phase‐contrast flow measurements at 3 T with the help of an in vitro model and to compare the results with data from two 1.5‐T scanners.

Evaluation of left ventricular diastolic function by pulsed Doppler tissue imaging in mice.

BACKGROUND Diastolic left ventricular (LV) function is commonly characterized by transmitral flow pattern in human beings. Recently, Doppler tissue imaging (DTI) was introduced to evaluate diastolic function. The aim of our study was to validate DTI in the evaluation of diastolic function in mice. METHODS We measured indices of diastolic function using pulsed DTI, and transmitral Doppler and LV pressure and its maximal rate of decrease (LVdP/dt(min)), before and 4 weeks after aortic banding in C57BL/6 mice. RESULTS Peak early diastolic velocity and ratio of peak early-to-late filling velocities, both measured by DTI, were significantly reduced after banding, thereby indicating diastolic dysfunction. Diastolic dysfunction was confirmed by impaired LV dP/dt(min), decreased transmitral early filling velocity, and transmitral early-to-late filling velocity ratio using transmitral Doppler. CONCLUSION DTI detects diastolic dysfunction caused by chronic pressure overload in mice after aortic banding. DTI is suggested to be implemented as part of routine mouse echocardiography for evaluation of LV diastolic function.

Long-term effects of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: 5-year results from the randomized-controlled BOOST trial—an echocardiographic study

AIMS We have recently observed that intracoronary autologous bone marrow cell (BMC)-transfer improves parameters of diastolic function in patients after acute myocardial infarction at 6 and 18 months. There is no clinical study addressing the long-term effect of BMC transfer on diastolic function. Therefore, we conducted a 5-year follow-up of the BOOST trial to evaluate a sustained benefit on echocardiographic parameters on diastolic function. METHODS AND RESULTS After successful primary percutaneous coronary intervention (PCI) for acute ST-elevation MI, patients were randomized to a control (n = 28) or BMC transfer group (n = 28). Echocardiography was performed at 4.5 +/- 1.5 days after PCI, at 6, 18, and 60 months. Diastolic function was determined by measuring transmitral flow velocities (E/A ratio), diastolic myocardial velocities (E(a)/A(a) ratio), isovolumic relaxation time (IVRT), and deceleration time (DT). All analyses were performed in a blinded fashion. There was an overall treatment effect of BMC transfer on E/A (0.25 +/- 0.10; 95% CI 0.05-0.44; P = 0.01). E/A ratio was significantly lower at 6 (Control 0.90 +/- 0.07; BMC 1.23 +/- 0.14; P = 0.03) and 18 months (Control 0.87+/-0.04; BMC 1.13 +/- 0.09; P = 0.01) in the control group, whereas E/A ratio was not different at 60 months between both groups (Control 0.90 +/- 0.06; BMC 1.05 +/- 0.07; P = 0.12). We found no overall effect of BMC transfer on E(a)/A(a) ratio (0.21 +/- 0.14; 95% CI -0.03 to 0.46; P = 0.09), DT (-12 +/- 11 ms; 95% CI -21 to 28; P = 0.75), IVRT -6 +/- 7 ms; 95% CI -9 to 19; P = 0.43), and E/E(a) ratio (0.58 +/- 0.88; 95% CI -1.18 to 2.34; P = 0.51). CONCLUSION Intracoronary autologous BMC transfer provides an overall treatment effect on echocardiographic parameters of diastolic function in patients after AMI. However, this effect is basically related to an early improvement of parameters of diastolic function without a sustained effect on long-term follow-up.

Bone-marrow-derived cell transfer after ST-elevation myocardial infarction: lessons from the BOOST trial.

Emerging evidence suggests that bone-marrow-derived stem and progenitor cells can be used to improve cardiac function after acute myocardial infarction. We tested this concept in the randomized, controlled, BOOST (bone marrow transfer to enhance ST-elevation infarct regeneration) clinical trial. Following successful percutaneous coronary intervention for acute ST-elevation myocardial infarction, patients received an intracoronary transfer of autologous bone marrow cells (BMCs). After 6 months, global left ventricular ejection fraction, as determined by magnetic resonance imaging, was significantly improved in the BMC-treated group compared with the control group. BMC transfer enhanced left ventricular systolic function, primarily in myocardial segments adjacent to the infarcted area, and also had a positive effect on diastolic function. BMC transfer did not increase the risk of adverse clinical events and did not promote in-stent re-stenosis or proarrhythmic effects. In principle, the effects of BMC transfer on ejection fraction were sustained at 18-month follow-up. Notably, radioactive labeling of BMCs and positron emission tomography showed that these beneficial effects are achieved with limited cardiac homing of BMCs after intracoronary application. Taken together, our studies indicate that intracoronary transfer of autologous BMCs is a safe, promising, and novel approach to further improving systolic function in patients with successful reperfusion after acute myocardial infarction.

Effects of Anesthesia on Diastolic Function in Mice Assessed by Echocardiography

Background: Transthoracic echocardiography is the predominant diagnostic tool to evaluate systolic and diastolic cardiac function noninvasively in mice. It is known that systolic function is substantially influenced by anesthetic agents used for sedation during echocardiography. However, the effect on diastolic function has not been investigated yet. The following study was conducted to evaluate the influence of different agents on diastolic left ventricular function in mice. Methods and Results: The effect of ketamine/xylazine (K/X), ketamine/midazolam (K/M), and tribromoethanol (TBE, Avertin) on diastolic function was measured 5, 15, and 25 minutes after the onset of anesthesia. Ratio of peak early‐to‐late myocardial diastolic velocities (Ea/Aa; determined by tissue Doppler imaging; TDI), ratio of peak transmitral early (E)‐ and late‐diastolic velocity (E/A), deceleration time (DT), and isovolumic relaxation time (IVRT) correlated significantly with heart rate (HR). Overall, increasing HR contributed to a decrease of E/A‐, Ea/Aa ratio, IVRT, and DT, whereas agents characterized by the strongest variation of HR (K/M and TBE) were associated with the greatest effect on diastolic function. Conclusion: Left ventricular diastolic function in mice, determined by echocardiography, is dependent on anesthetic agent and timing of measurements after onset of anesthesia.

Aerobic training in adults after atrial switch procedure for transposition of the great arteries improves exercise capacity without impairing systemic right ventricular function.

BACKGROUND Exercise training safely and efficiently improves symptoms in patients with heart failure due to left ventricular dysfunction. However, studies in congenital heart disease with systemic right ventricle are scarce and results are controversial. In a randomised controlled study we investigated the effect of aerobic exercise training on exercise capacity and systemic right ventricular function in adults with d-transposition of the great arteries after atrial redirection surgery (28.2 ± 3.0 years after Mustard procedure). METHODS 48 patients (31 male, age 29.3 ± 3.4 years) were randomly allocated to 24 weeks of structured exercise training or usual care. Primary endpoint was the change in maximum oxygen uptake (peak VO2). Secondary endpoints were systemic right ventricular diameters determined by cardiac magnetic resonance imaging (CMR). Data were analysed per intention to treat analysis. RESULTS At baseline peak VO2 was 25.5 ± 4.7 ml/kg/min in control and 24.0 ± 5 ml/kg/min in the training group (p=0.3). Training significantly improved exercise capacity (treatment effect for peak VO2 3.8 ml/kg/min, 95% CI: 1.8 to 5.7; p=0.001), work load (p=0.002), maximum exercise time (p=0.002), and NYHA class (p=0.046). Systemic ventricular function and volumes determined by CMR remained unchanged. None of the patients developed signs of cardiac decompensation or arrhythmias while on exercise training. CONCLUSIONS Aerobic exercise training did not detrimentally affect systemic right ventricular function, but significantly improved exercise capacity and heart failure symptoms. Aerobic exercise training can be recommended for patients following atrial redirection surgery to improve exercise capacity and to lessen or prevent heart failure symptoms. ( CLINICAL TRIAL REGISTRATION ClinicalTrials.gov #NCT00837603).