Skip Navigation


European Heart Journal Advance Access originally published online on June 4, 2008
European Heart Journal 2008 29(15):1819-1826; doi:10.1093/eurheartj/ehn233
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/15/1819    most recent
ehn233v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Baldazzi, F.
Right arrow Articles by Kastrup, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Baldazzi, F.
Right arrow Articles by Kastrup, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Release of biomarkers of myocardial damage after direct intramyocardial injection of genes and stem cells via the percutaneous transluminal route

Federica Baldazzi1, Erik Jørgensen1, Rasmus S. Ripa1 and Jens Kastrup1,2,3,*

1 Cardiac Catheterisation Laboratory 2014, Department of Cardiology, The Heart Centre, Rigshospitalet, University Hospital Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark
2 Cardiac Stem Cell Research Laboratory, Department of Cardiology, The Heart Centre, Rigshospitalet, University Hospital Copenhagen, Copenhagen, Denmark
3 Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

Received 12 October 2007; revised 9 May 2008; accepted 15 May 2008; online publish-ahead-of-print 4 June 2008.

* Corresponding author. Tel: +45 3545 2819/2817, Fax: +45 3545 2705, Email: jkastrup{at}rh.regionh.dk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions and implications
 Funding
 References
 
Aims: We aimed to quantify the release of biomarkers of myocardial damage in relation to direct intramyocardial injections of genes and stem cells in patients with severe coronary artery disease.

Methods and results: We studied 71 patients with ‘no-option’ coronary artery disease. Patients had, via the percutaneous transluminal route, a total of 11 ± 1 (mean ± SD) intramyocardial injections of vascular endothelial growth factor genes (n = 56) or mesenchymal stromal cells (n = 15). Injections were guided to an ischaemic area by electromechanical mapping, using the NOGATM/MyostarTM catheter system. Plasma CKMB (upper normal laboratory limit = 5 µg/L) was 2 µg/L (2–3) at baseline; increased to 6 (5–9) after 8 h (P < 0.0001) and normalized to 4 (3–5) after 24 h. A total of eight patients (17%), receiving a volume of 0.3 mL per injection, had CKMB rises exceeding three times the upper limit, whereas no patient in the group receiving 0.2 mL had a more than two-fold CKMB increase. No patient developed new ECG changes. There were no clinically ventricular arrhythmias and no death.

Conclusion: NOGA mapping followed by direct intramyocardial injections of stem cells or genes lead to measurable release of cardiac biomarkers compared with NOGA mapping alone. The increase in biomarkers was related to the injected volume.

Key Words: Stem cells therapy • Gene therapy • Myocardial enzymes • NOGA system • Intramyocardial injection


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions and implications
 Funding
 References
 
Patients who present with advanced occlusive coronary artery disease and refractory angina and no options for medication improvements, or revascularization with percutaneous coronary intervention (PCI), or coronary artery by pass grafting (CABG), are a challenge in clinical cardiology.1,2 A number of experimental therapies aiming to induce neovascularization in ischaemic areas of the myocardium have been suggested. Therapies with direct intramyocardial injections of genes encoding vascular growth factors or stem cells from the bone marrow have been evaluated in patients with coronary artery disease. However, the results have been conflicting.3,4 Direct intramyocardial injections of bone-marrow-derived stem cells and angiogenic genes in patients have been reported to be safe in small patient populations.5 Though, there have been some doubts on the safety of intramyocardial injections of skeletal myoblasts and, also, in a recent report in an animal model, ventricular arrhythmias were not frequent, in relation to intramyocardial injections of bone-marrow-derived stem cells.4–8

We aimed to study the safety of direct intramyocardial injections of stem cells or genes, via the percutaneous transluminal route, in patients with severe coronary artery disease, and in particular to quantify the release of bio-markers of myocardial damage.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions and implications
 Funding
 References
 
Data from all 71 patients included in our centre in controlled clinical trials with direct intramyocardial injections of genes or stem cells were included in the analyses. We compare these data with those of a control group of 25 patients who after their combined NOGA and injection procedure had a prescribed 3 months follow-up diagnostic NOGA-mapping procedure (mapping only, without injection) per protocol. These 25 patients belonged to one of the four studies analysed (EUROINJECT One Trial).9 Forty-eight patients were included in two previously published studies using intramyocardial injections of genes encoding vascular endothelial growth factor VEGF-A165.9,10 The gene therapy studies were approved by the Ethical Committee (02-078/00, 02-053/01) and Danish Medicines Agency (2612-1490, 2612-1782).9,10 Eight patients came from the terminated multi-centre NOVATM trial, a randomized, double blind, placebo-controlled study evaluating the efficacy of BIOBYPASS® (AdGVVEGF121.10NH). The NOVATM trial was approved by the Ethical Committee (KF 02 084/04), the Danish Medicines Agency (Eudra CT 2004-001250-91), and registered in www.clinicaltrial.gov (NCT00215696 [ClinicalTrials.gov] ). In the NOVA trial, a total of 17 patients were included before the company terminated the trial due to a business decision. We included eight of the 17 patients in the trial at our site. It is these eight patients who were included in the present analyses. The study was still blinded when performing the present analyses.

Fifteen patients came from an ongoing trial evaluating the safety and efficacy of direct intra-myocardial injection of autologous in vitro expanded mesenchymal stromal cells. Also, this study is approved by the Ethical Committee (KF 02-268856), the Danish Medicines Agency (Eudra CT 2005-002657-45), and registered in www.clinicaltrial.gov (NCT00260338 [ClinicalTrials.gov] ). The trial is ongoing and the analyses included all patients enrolled in the study at the time of the present analyses.

The unpublished and ongoing studies followed the same recruitment procedures of the published studies. The end point for these studies (NOVA trial unpublished and MSC trial ongoing) is to evaluate the effect of the gene or stem cells therapy on the myocardial function. During follow-up, all patients had undergone non-invasive tests (SPECT and echocardiogram) to assess the ejection fraction and the regional left ventricular motion after treatment. Secondary end point is to evaluate the safety of the treatment. All patients received oral and written information about the studies and signed an informed consent.

Participating patients
The patients included have been selected, treated, and followed by the Cardiac Catheterization Laboratory, Department of Cardiology at Righospitalet. All four studies have the same inclusion and exclusion criteria. Patients included had no options for conventional revascularization therapy, and also had the following characteristics. (1) Reversible ischaemia at stress single photon emission computerized tomography (SPECT). (2) A myocardial thickness of 8 mm or more in the injection area measured by echocardiography. (3) At least one coronary artery or patent graft from which new collaterals/vessel could be supplied. (4) Canadian Cardiovascular Society class 2 or 3 angina.

Excluded patients had (i) ejection fraction <40%, (ii) unstable angina pectoris, (iii) acute myocardial infarction within the last 3 months, (iv) diabetes mellitus with proliferative retinopathy, or (v) been diagnosed or suspected to have cancer disease or any other serious concomitant disease.

All the patients were treated with conventional drug therapy according to guidelines.11,12

Intramyocardial injection procedures
A dedicated team of two senior cardiologists and three nurses performed all procedures using the NOGATM Unix® system (Biosense Webster A/S, Johnson and Johnson) or, from 2006 and onwards, the NOGATM XP® system (Biologic Delivery SystemsTM, Cordis Corporation) and the 8-french-sized Myostar® mapping-injection catheter. Intramyocardial injections were administered, as previously described, slowly (30–40 s) into an ischaemic area of the left ventricle with a thickness of >8 mm.9,10 The injection area was delineated by combining information from an electromechanical map, a single photon emission scientigraphy, and a recent coronary angiography. In 25 patients, we performed a protocol defined diagnostic NOGATM follow-up 3 months after the injection procedure to evaluate the effect of the treatment. After each procedure, an echocardiography, focusing on pericardial effusion, was performed. Patients were discharged the day after the injection/diagnostic NOGATM procedure.

Blood samples
All enrolled patients had a blood test done before the invasive procedure. After the invasive procedure, the blood samples for plasma CKMB and TNT measurements were collected after 8 and 24 h. If the CKMB level after 24 h was above the upper normal limit (5 µg/L) then blood sampling was repeated until the normalization of the parameter. A CKMB level of more than three times the upper laboratory limits (5 µg/L) was considered a procedural myocardial infarction.13,14

Arrhythmia monitoring
All patients were ECG-monitored for 24 h in-hospital by special dedicated staff with no other assignments besides ECG monitoring. The morning after the procedure a report on the ECG monitoring and on eventual arrhythmias were presented to the cardiologist responsible for the medication and the discharge of the patient. Ventricular extra systoles were not quantified.

Statistical analysis
Continuous variables with a normal distribution are presented as mean (± standard deviation) and the variables with a non-Gaussian distribution are presented as median (first quartile–third quartile). The qualitative variables are presented as numbers and percentages. Change in CKMB and TNT following intramyocardial injections (Figure 1) was analysed in an ANOVA with the repeated measure as a within-subject factor. The Greenhouse-Geisser (Box) correction was applied to account for compound symmetry. To account for the type of procedure (Figure 2), this was subsequently included into the repeated measures ANOVA as a between-subjects factor.


Figure 1
View larger version (5K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Plasma concentrations of CKMB (A) and TNT (B) before, 8 and 24 h after the combined NOGA-mapping and injection procedure. There was a significant increase in both CKMB (P < 0.001) and TNT (P < 0.001) at 8 h and for TNT at 24 h (P < 0.001) by repeated measures ANOVA. Numbers are median (first quartile–third quartile).

 

Figure 2
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2 Comparison of CKMB concentration in 25 patients with both a baseline combined NOGA-mapping and injection procedure (black rhombus), and a follow-up diagnostic NOGA procedure without injection 3 months later (gray square). There was a significant interaction (P = 0.001) between time and type of procedure indicating that intramyocardial injections cause the increase in CKMB and not the mapping procedure. Numbers are median (first quartile–third quartile).

 
Associations between (i) products injected, (ii) volume per injection, (iii) total volume injected and change in CKMB was analysed by three independent one-way ANOVA/ANCOVA.

Independent-sample Student’s t-test has been used to compare unpaired groups and paired Student’s t-test to compare two paired groups for the variables with a Gaussian distribution. The variable with a non-Gaussian distribution has been tested by the non-parametric Mann–Whitney test for two unpaired groups and Wilcoxon signed-rank test for two paired groups.

All data were analysed using SPSS statistical analysis program (SPSS version 15.0, SPSS Inc., Chicago, Il, USA) using two-sided tests. Values of P < 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions and implications
 Funding
 References
 
Baseline characteristics
The four trials, in which the patients were included and treated with either genes encoding VEGF or mesenchymal stromal cells, are summarized in Table 1. Clinical baseline characteristics and procedural data are shown in Table 2.


View this table:
[in this window]
[in a new window]

  		Table 1 Studies included in the analyses

 

View this table:
[in this window]
[in a new window]

  		Table 2 Demographic characteristics and procedural data

 
Cardiac marker release
We found a small and brief, but significant plasma CKMB (P < 0.001) and TNT (P < 0.001) increase after the combined NOGATM mapping and injection procedure (Figure 1). There was a significant increase of 6.8 µg/L (95% CI 4.6–9.0) and 0.12 µg/L (95% CI 0.08–0.16) for CKMB and TNT, respectively, from baseline to 8 h post-procedure. CKMB then normalized 24 h after the procedure (Figure 1A). Plasma TNT also decreased 24 h post-procedure, but it was still above normal limit (Figure 1B).

A subgroup of 25 patients had both a NOGATM mapping and injection procedure, and at 3 months had a follow-up diagnostic NOGATM mapping procedure without injection. We found a significant main effect of the type of procedure (injection or mapping alone) on increase in CKMB (P = 0.008). Also, a significant interaction between time and type of procedure was obtained (P = 0.001) (Figure 2), indicating a significantly larger increase in CKMB following injection compared with mapping alone. This was further confirmed by a post hoc analysis showing a mean difference in the increase of 9.6 µg/L (95% CI 4.1–15.1) from baseline to 8 h post-procedure.

There was no difference in enzyme release between patients who had 0.2 mL of mesenchymal stromal cell solution vs. patients who had 0.2 mL of adVEGF injections [5 (4–6) and 7 (3.8–8.5), respectively, P = 0.27]. Patients, who received 0.2 mL (n = 23) volume for each injection, had a significant lower enzyme release than patients who received 0.3 mL injection volume (n = 48) (Figure 3A and B). We found no correlation between procedure time and CKMB release (P = 0.76, R2 = 0.003). However, there was a tendency towards higher CKMB values with increasing total volume injected per procedure (Figure 3C). Only volume injected at each site was significantly associated with CKMB rise by univariate analysis.


Figure 3
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 3 Relation between volume per intramyocardial injection and (A) plasma CKMB concentration and (B) plasma CKMB concentration divided by number of injections showing a significant difference of 6.7 µg/L (95% CI 2.0–11.4, P = 0.006) and 0.69 µg/L (0.23–1.16, P = 0.004) for CKMB and TNT, respectively. (C) Correlation between total volume injected and plasma concentration of CKMB 8 h post-procedure. *Number of injections for 0.2 mL (12.4 ± 0.9); **Number of injections for 0.3 mL (10.7 ± 0.7) P < 0.0001. Numbers are median (first quartile–third quartile).

 
A total of eight patients had CKMB values more than three times the upper limit of CKMB and five of them had an increase more than five times the upper limit of CKMB, (CKMB >25 µg/L), at 8 h after the injection procedure. All these patients received 0.3 mL per injection. The mean of total volume injected and the number of injections for these patients were 3.2 ± 0.16 and 10.6 ± 0.55, respectively. The patients were followed in protocols for 12 months without development of any serious cardiac event.

NOGATM, injection procedure and short-term follow-up
The correlation between electromechanical mapping procedure time and team experience and between injection procedure time and team experience is depicted in Figure 4. This figure shows a significant negative correlation between procedure time and increasing team experience.


Figure 4
View larger version (8K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 4 Correlation between diagnostic NOGA-mapping procedure time and operator’s experience (A) and between injection time and operator’s experience (B). 95% CIs indicated.

 
ECG-monitoring post-procedure and clinical follow-up
There were no procedural myocardial perforations, and no post-procedural pericardial effusions. One patient developed atrial fibrillation, most likely induced by the electromechanical mapping catheter. This arrhythmia persisted for some hours in the post-procedural period, but converted spontaneously to sinus rhythm before discharge the following day. One patient with a known second degree AV block had progression to third degree AV block requiring permanent pacemaker therapy. Injections in this patient were performed in the lateral wall. Two patients needed antibiotic treatment in the immediate follow-up period. There were no ventricular tachycardia reported post-procedure. No patient required a change of medication due to ventricular arrhythmias or cardioverter/defibrillator implantation in the follow-up period. In the first 6 months after the procedures, there was no sudden cardiac death. One patient died in this period by progressive heart failure.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions and implications
 Funding
 References
 
The main finding of the present study is that a cardiac enzyme release can be measured 8 h after a direct intramyocardial injection procedure. This enzyme release seems related to the volume injected. The enzymes normalized the day after the procedure. Intraventricular catheter movements, in relation to a diagnostic electromechanical mapping procedure, which precedes intramyocardial injections, do not seem to lead to enzyme release exceeding the normal upper limits. The procedure time decreases with the increasing experience of the operators. However, there was no relation between the procedure time and the changes in plasma enzymes.

Although significant, the measured cardiac enzyme release was small, for CKMB in average in the order of twice the upper normal limit, and there were no signs of clinical important side effects to this minor myocardial trauma. Guidelines of percutaneous coronary interventions consider a procedural myocardial infarction of importance to prognosis, and a CKMB increase of 3 or 5 times the upper laboratory limit as significant.13,14 In our study, 17% of patients treated with a volume of 0.3 mL per injection developed a more than three times increase of CKMB. Whereas, patients receiving 0.2 mL per injection did not have CKMB release exceeding two times the upper normal limit. Furthermore, our data seem to show that a volume of 0.3 mL per injection leads to an increase in CKMB, which is more than twice the increase after an injection of 0.2 mL (Figure 3B). Therefore, it seems that injection volumes of 0.2 mL are safer than 0.3 mL. It could be considered as a limitation in the study or a benefit for the study, that two of the studies included used 0.3 mL for each injection, and two studies used 0.2 mL for each injection. As outlined in Figure 3, this leads to heterogeneity in CKMB release between the studies. It is our hypothesis that this heterogeneity is caused by the difference in volume injected and not the study, because similar patients were included and treatment staff as well as the equipment were the same. A few patients had CKMB increases more than 3 and 5 times the upper normal limit. The patients were followed in protocols for 12 months without development of any serious cardiac event. Therefore, the CKMB increase was not related to any clinical event, but was likely a consequence and indication of the intramyocardial delivery of a treatment substance. A diagnostic NOGA-mapping procedure only without injection, as performed at follow-up in the EUROINJECT One Trial, induces a small increase in CKMB below the normal limit, indicating that this procedure is safe.

These results might serve as a reference in the planning of future studies using intramyocardial injections.

Four other relatively small clinical studies on a total of 43 patients have used intramyocardial injections of a volume of 0.3 mL or more.15–18 Results are contradictory. Losordo et al.16 injected a total of 6 mL plasmid VEGF-2 using six injections in 19 patients and found no CKMB rise above the normal limit. Whereas, Fuchs et al.15 found minor CKMB and TNT rises in half of their 10 patients receiving nine injections of 0.3 mL AdVEGF-121 each. Vale et al.17 and Briguori et al.18 did not report data on cardiac biomarkers in their injection studies using 1 and 0.5 mL per injection, respectively.

Recently, an animal experiment using rats weighing 150–200 g, reported an increase in ventricular arrhythmias after direct intramyocardial injection of mononuclear bone-marrow cells, when compared with retrograde intracoronary delivery.6 They injected a total volume of 0.2 mL intramyocardially, which probably compares with 25–50 times the intramyocardially injected volumes in the human studies mentioned in Table 3.19–23 Therefore, we are tempted to hypothesize, based on the observations presented in Figure 3, that the injected volume matters for the myocardial damage produced in this study, and that the arrhythmias found could be, at least partly, explained by myocardial damage secondary to the relatively large injection volume used. However, several differences in morphological and electrophysiological properties exist between rat and human myocardium and for this reason it might be difficult to compare the different reaction with the actual noxa.24


View this table:
[in this window]
[in a new window]

  		Table 3 Studies with direct intramyocardial injection using the NOGA system

 
In none of the clinical studies on intramyocardial injections of VEGF and bone-marrow cells in patients presented in Table 3 there were increased tendency to arrhythmias. However, experimental and clinical studies on intramyocardial transplantation of skeletal myoblast, which repeatedly have documented engraftment in scar tissue, and associated improvement in left ventricular function might lead to malignant arrhythmic events and need of cardioverter/defibrillator treatment. These arrhythmias are late and do not seem to be related to the injection trauma.4,5 No arrhythmia was detected in the present studies.

A limitation in the analyses is that dose and study are correlated. Thus, if we adjust for study, we will also indirectly adjust for dose. However, it was an objective to test if dose was a predictor and that cannot be tested if we at the same time adjust for it. This poses the limitation that we cannot with certainty say if dose or study is the independent predictor. However, since NOGA procedure design was identical between the trials, we find it most likely that the dose is the independent predictor. Another limitation is that the clinical impact of the CKMB rise during NOGA injection procedures is unknown. However, it seems from the present data that it could be identical to the low impact of CKMB rise during percutaneous coronary interventions.


   Conclusions and implications
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions and implications
Funding
 References
 
Direct intramyocardial injections of genes and stem cells seem relatively safe. Injections are accompanied by a minor release of cardiac biomarkers of myocardial damage. The cardiac enzyme rise is related to the volume injected. If injection volume is limited to 0.2 mL per injection, and the number of injections from 10 to 12, the plasma CKMB level never exceeds three times the upper normal limit. Using this injection regimen, patients would not be considered having had a procedural myocardial infarction, and extended hospital stay, control diagnostic angiography, and anticoagulation regimens would not be required.

Conflict of interest: J.K. is consultant for Biologics Delivery Systems, Cordis Corporation. The authors have nothing else to declare.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions and implications
 Funding
References
 
Biologics Delivery Systems, Cordis Corporation and GenVec Inc. was the initiator and sponsor of the NOVA trial. Private funding from The Danish Heart Foundation, The Lundbeck Foundation, Aase and Ejnar Danielsens Foundation, The Toyota Foundation, Brdr. Hartmans Foundation, Søren and Helene Hempels Foundation Research Foundation at Rigshospitalet and Danish Medical Research Council sponsored the other trials. Cordis Europe, Johnson & Johnson sponsored the injection catheters to Euroinject One trial.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions and implications
 Funding
 References
 

  1. Fuchs S, Battler A, Kornowski R. Catheter-based stem cell and gene therapy refractory myocardial ischemia. Nat Clin Pract Cardiovasc Med (2007) 4(Suppl. 1):S89–S95.[CrossRef][Medline]
  2. Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T, Zheng ZJ, Flegal K, O'Donnell C, Kittner S, Lloyd-Jones D, Goff DC Jr, Hong Y, Adams R, Friday G, Furie K, Gorelick P, Kissela B, Marler J, Meigs J, Roger V, Sidney S, Sorlie P, Steinberger J, Wasserthiel-Smoller S, Wilson M, Wolf P, American Heart Association Statistic Committee Stroke Statistics Subcommittee. Heart disease and stroke statistic 2006 update: a report from the American Heart Association Statistics Committee and stroke statistics subcommittee. Circulation (2006) 113:e85–e151.[Free Full Text]
  3. Mannheimer C, Camici P, Chester MR, Collins A, DeJongste M, Eliasson T, Follath F, Hellemans I, Herlitz J, Luscher T, Pasic M, Thelle D. The problem of chronic refractory angina: report from the ESC Joint Study Group on the Treatment of refractory angina. Eur Heart J (2002) 23:355–370.[Free Full Text]
  4. Menasche P, Hagege AA, Vilquin JT, Desons M, Abergel E, Pozet B, Bel A, Sarateanu S, Scorsin M, Schwartz K, Bruneval P, Benbunan M, Marolleau JP, Duboc D. Autologus skeletal myoblast transplantation for severe post infarction left ventricular dysfunction. J Am Coll Cardiol (2003) 41:1078–1083.[Abstract/Free Full Text]
  5. Fernandes S, Amirault JC, Lande G, Nguyen JM, Forest V, Bignolais O, Lamirault G, Heudes D, Orsonneau JL, Heymann MF, Charpentier F, Lemarchand P. Autologus myoblast after myocardial infarction increases the inducibility of ventricular arrhythmias. Cardiovasc Res (2006) 69:348–358.[Abstract/Free Full Text]
  6. Fukushima S, Varela-Carver A, Coppen SR, Yamahara K, Felkin LE, Lee J, Barton PJ, Terracciano CM, Yacoub MH, Suzuki K. Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular arrhythmias in rat chronic ischemic heart failure model. Circulation (2007) 115:2254–2261.[Abstract/Free Full Text]
  7. Reinecke H, MacDonald GH, Hauschka SD, Murry CE. Electromechanical coupling between skeletal and cardiac muscle. Implication for infarct repair. J Cell Biol (2000) 149:731–740.[Abstract/Free Full Text]
  8. Fouts K, Fernandes B, Mal N, Liu J, Laurita KR. Electrophysiological consequence of skeletal myoblast transplantation in normal and infracted canine myocardium. Heart Rhythm (2006) 3:452–461.[CrossRef][Web of Science][Medline]
  9. Kastrup J, Jørgensen E, Ruck A, Tägil K, Glogar D, Ruzyllo W, Botker HE, Dudek D, Drvota V, Hesse B, Thuesen L, Blomberg P, Gyongyosi M, Sylven C, Euroinject One Group. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris. A randomized double-blind placebo-controlled study. The Euroinject One trial. J Am Call Cardiol (2005) 45:982–988.[CrossRef]
  10. Ripa RS, Wang Y, Jorgensen E, Johnsen HE, Hesse B, Kastrup J. Intramyocardial injection of vascular endothelium growth factor-A165 plasmid followed by granulocyte-colony stimulating factor treatment to mobilize stem cells and promote myocardial homing to induce angiogenesis in patients with severe chronic ischemic heart disease. Eur Heart J (2006) 27:1785–1792.[Abstract/Free Full Text]
  11. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fedmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B, American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial infarction); American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association of Cardiovascular and Pulmonary Rehabilitation; Society for Academic Emergency Medicine. ACC/AHA Guideline for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation (2007) 116:e148–e304.[Free Full Text]
  12. Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, Ferguson TB Jr, Fihn SD, Fraker TD Jr, Gardin JM, O'Rourke RA, Pastemak RC, Williams SV. American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol (2003) 41:159–168.[Free Full Text]
  13. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, Jacobs AK, Kem MJ, King SB III, Morrison DA, O'neill WWW, Schaff HV, Whitlow PL, Williams DO, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention-summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol (2006) 47:216–235.[Free Full Text]
  14. Silber S, Albertsson P, Avilés FF, Camici PG, Colombo A, Hamm C, Jørgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W. Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Guidelines for percutaneous coronary interventions. The task force for percutaneous coronary interventions of the European Society of Cardiology. Eur Heart J (2005) 26:804–847.[Free Full Text]
  15. Fuchs S, Dib N, Cohen BM, Okubagzi P, Diethrich EB, Campbell A, Macko J, Kessler PD, Rasmussen HS, Epatein SE, Kornowski R. A randomized, double-blind, placebo-controlled, multicenter, pilot study of the safety and feasibility of catheter-based intramyocardial injection of AdVEGF 121 in patients with refractory advanced coronary artery disease. Catheter Cardiovasc Interv (2006) 68:372–378.[CrossRef][Web of Science][Medline]
  16. Losordo DW, Vale PR, Hendel RC, Milliken CE, Fortuin FD, Cummings N, Schatz RA, Asahara T, Isner JM, Kuntz RE. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 3 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation (2002) 105:2012–2018.[Abstract/Free Full Text]
  17. Vale PR, Losordo DW, Milliken CE, McDonald MC, Gravelin LM, Curry CM, Esakof DD, Maysky M, Symes JF, Isner JM. Randomized, single-blind, placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia. Circulation (2001) 103:2138–2143.[Abstract/Free Full Text]
  18. Briguori C, Reimes B, Sarais C, Napodano M, Pescotto P, Azzarello G, Bregni M, Porcellini A, Vinante O, Zanco P, Peschle C, Condorelli G, Colombo A. Direct intramyocardial percutaneous delivery of autologous bone marrow in patients with refractory myocardial angina. Am Heart J (2006) 151:674–680.[CrossRef][Web of Science][Medline]
  19. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa GV, Mesquita CT, Belem L, Vaughn WK, Rangel FO, Assad JA, Carvalho AC, Branco RV, Rossi MI, Dohmann HJ, Willerson JT. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation (2004) 110:II213–II218.[Web of Science][Medline]
  20. Tse HF, Kwong YL, Chan JKF, Lo G, Ho CL, Lau CP. Angiogenesis in ischemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet (2003) 361:47–49.[CrossRef][Web of Science][Medline]
  21. Fuchs S, Kornowski R, Weisz G, Satler LF, Smits PC, Okubagzi P, Baffour R, Aggaewal A, Weissman NJ, Cerqueira M, Waksman R, Serruys P, Battler A, Moses JW, Leon MB, Epstein SE. Safety and feasibility of transendocardial autologous bone marrow cell transplantation in patients with advanced heart disease. Am J Cardiol (2006) 97:823–829.[CrossRef][Web of Science][Medline]
  22. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Carvalho AC, Dutra HS, Dohmann HJ, Silva GV, Belem L, Vivacqua R, Rangel FO, Esporcatte R, Geng YJ, Vaughn WK, Assad JA, Mesquita ET, Willerson JT. Transendocardial, autologous bone marrow cells transplantation for severe, chronic ischemic heart failure. Circulation (2003) 107:2294–2302.[Abstract/Free Full Text]
  23. Losordo DW, Schatz RA, White CJ, Udelson JE, Veereshwarayya V, Durgin M, Poh KK, Weinstein R, Kearney M, Chaudhry M, Burg A, Eaton L, Heyd L, Thorne T, Shturman L, Hoffmeister P, Story K, Zak V, Dowling D, Traverse JH, Olson RE, Flanagan J, Sodano D, Murayama T, Kawamoto A, Kusano KF, Wollins J, Welt F, Shah P, Soukas P, Asahara T, Henry TD. Intramyocardial transplantation of autologous CD34 stem cells for intractable angina. A phase I/IIa double-blind, randomized controlled trial. Circulation (2007) 115:3165–3172.[Abstract/Free Full Text]
  24. Doggrell SA, Brown L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res (1998) 39:89–105.[Free Full Text]
    The above article uses a new reference style being piloted by the EHJ that shall soon be used for all articles.

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 CirculationHome page
P. Menasche
Stem Cell Therapy for Heart Failure: Are Arrhythmias a Real Safety Concern?
Circulation, May 26, 2009; 119(20): 2735 - 2740.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/15/1819    most recent
ehn233v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Baldazzi, F.
Right arrow Articles by Kastrup, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Baldazzi, F.
Right arrow Articles by Kastrup, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?