Noninvasive Quantification and Optimization of Acute Cell Retention by In Vivo Positron Emission Tomography After Intramyocardial Cardiac-Derived Stem Cell Delivery

Q: What are the key findings of this study?

Sealing injection sites with fibrin glue or administering adenosine doubled acute myocardial CDC retention by PET (37.5% and 35.4% vs 17.8% in PBS, p<0.01 and p<0.05).

Q: What is the clinical evidence from this study?

Population: Myocardial infarction (permanent left anterior descending coronary artery ligation in rats) (n=85). Intervention: Intramyocardial 18FDG-labeled cardiac-derived stem cells (CDCs) with epicardial fibrin glue, intravenous adenosine, cardiac arrest, or 2,3-butanedione-2-monoxime vs. Intramyocardial 18FDG-labeled CDCs suspended in plain PBS. Primary outcome: Acute myocardial cell retention at 1 hour post-injection quantified by in vivo 18FDG PET (p=<0.01).

Q: What does this research mean for the field?

Sealing intramyocardial injection sites with epicardial fibrin glue or slowing heart rate with adenosine doubles acute retention of cardiac-derived stem cells in infarcted myocardium. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To noninvasively quantify acute myocardial retention of cardiac-derived stem cells using positron emission tomography and evaluate strategies to improve delivery efficiency.

John V. Terrovitis; Riikka Läutamaki; Michael J. Bonios; James M. Fox; James M. Engles; Jianhua Yu; Michelle K. Leppo; Martin G. Pomper; Richard L. Wahl; Jürgen Seidel; Benjamin M. W. Tsui; Frank Michael Bengel; Maria Roselle Abraham; Eduardo Marbán

doi:10.1016/j.jacc.2009.04.097

October 1, 2009Journal of the American College of CardiologyOpen Access

Noninvasive Quantification and Optimization of Acute Cell Retention by In Vivo Positron Emission Tomography After Intramyocardial Cardiac-Derived Stem Cell Delivery

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Key result

Fibrin glue or adenosine roughly doubles acute myocardial stem cell retention after intramyocardial delivery.

P<0.01
n=85

Why the study?

Stem cell transplantation for cardiac regeneration is limited by low cell retention and engraftment, and a clinically applicable method to accurately quantify cell retention is needed to optimize delivery.

Does sealing the epicardial injection site with fibrin glue or slowing ventricular rate with intravenous adenosine improve acute myocardial retention and 3-week engraftment of intramyocardially delivered cardiac-derived stem cells in a rat myocardial infarction model?

Key Points

To noninvasively quantify acute myocardial retention of cardiac-derived stem cells using positron emission tomography and evaluate strategies to improve delivery efficiency.
Cardiac-derived stem cells (CDCs) isolated from male Wistar Kyoto rats were radiolabeled with 18FDG and injected intramyocardially into female syngeneic rats after permanent coronary artery ligation.
Interventions to reduce cell washout included epicardial application of fibrin glue, adenosine-induced bradycardia, and injection during cardiac arrest.
Retention at 1 hour post-injection was imaged by 18FDG PET and validated by real-time quantitative PCR targeting the male-specific SRY gene, with engraftment assessed at 3 weeks.
Myocardial retention of CDCs in plain PBS 1 hour after injection was 17.8±7.3% by PET and 17.6±11.5% by quantitative PCR.
Delivery during cardiac arrest achieved 75.6±18.6% retention, while adenosine-induced bradycardia (35.4±5.3%, P<0.05) and epicardial fibrin glue (37.5±8.2%, P<0.01) each roughly doubled acute retention compared to PBS alone.
Quantitative PCR at 3 weeks demonstrated significantly higher cell engraftment in the fibrin glue group compared to PBS (22.1±18.6% vs 5.3±3.1%, P=0.039).

Structured PICO

Does sealing the epicardial injection site with fibrin glue or slowing ventricular rate with intravenous adenosine improve acute myocardial retention and 3-week engraftment of intramyocardially delivered cardiac-derived stem cells in a rat myocardial infarction model?

P

Population

85 female Wistar Kyoto rats with experimental myocardial infarction induced by permanent left anterior descending coronary artery ligation, followed for up to 21 days.

I

Intervention

Intramyocardial injection of 2 million 18FDG-labeled cardiac-derived stem cells (CDCs) in 150 µl PBS at two sites in the infarct/border zone, combined with delivery optimization strategies: epicardial fibrin glue (1-2 drops over injection site, n=8 PET / n=11 echo), intravenous adenosine (1 mg immediately before delivery, n=4), combined IV adenosine and epicardial fibrin glue (n=8), thiopental-induced cardiac arrest (n=4), or local 100 µM 2,3-butanedione-2-monoxime (BDM, n=6).

C

Comparator

Intramyocardial injection of 2 million 18FDG-labeled CDCs suspended in 150 µl plain PBS without delivery optimization (n=8 PET / n=11 echo), plus vehicle-only controls (PBS only n=9, PBS + epicardial fibrin glue n=8) for functional echo studies.

O

Outcome

Acute myocardial cell retention at 1 hour after intramyocardial delivery, quantified noninvasively by in vivo 18FDG PET imaging (as % of net injected radioactivity) and validated by real-time quantitative PCR for the male-specific SRY gene.surrogate

Main Result

Absolute Event Rate: 37.5% vs 17.8%

p-value: p=<0.01

In vivo 18FDG PET accurately quantifies acute intramyocardial stem cell retention and demonstrates that epicardial fibrin glue sealing and intravenous adenosine each double acute cell retention, with fibrin glue quadrupling 3-week cell engraftment.

Limitations

Short half-life of 18FDG (110 min) restricts PET cell tracking to the first few hours after delivery.
Small animal (rat) model has higher heart rates and larger relative injectate-to-myocardial mass volume than humans, requiring validation in large animal models.
Long-term engraftment and cardiac functional impact were not assessed in the adenosine group.
Large variability in fractional area change measurements limited statistical power to detect significant functional differences between fibrin glue and PBS cell groups.
Short half-life of 18FDG (110 min) limits PET tracking to the first few hours after cell delivery
Small animal (rat) model with high baseline heart rate (300-400 bpm) and larger relative injectate volume compared to human myocardium
PET availability is limited to larger centers
Long-term engraftment and cardiac function were not evaluated in the adenosine group

Implication

May enhance acute CDC retention in rat MI models; hypothesis-generating for optimizing intramyocardial delivery before clinical trials.

Abstract

Objectives To quantify acute myocardial retention of cardiac-derived stem cells (CDCs) and evaluate different delivery methods using Positron Emission Tomography (PET). Background Success of stem cell transplantation for cardiac regeneration is partially limited by low retention/engraftment of the delivered cells. A clinically applicable method for accurate quantification of cell retention would enable optimization of cell delivery. Methods CDCs derived from syngeneic, male Wistar Kyoto (WK) rats were labeled with 18FDG and injected intramyocardially into the ischemic region of female WK rats following permanent left coronary artery ligation. The effects of fibrin glue, bradycardia (adenosine) and cardiac arrest were examined. 18FDG PET was performed for quantification of cell retention. Quantitative PCR for the male-specific SRY gene was performed to validate the PET results. Results Myocardial retention of cells suspended in PBS 1 hr after delivery was 17.6±11.5% by PCR and 17.8±7.3% by PET. When CDCs were injected immediately following induction of cardiac arrest, retention was increased to 75.6±18.6%. Adenosine slowed the ventricular rate and doubled CDC retention (35.4±5.3%). A similar increase in CDC retention was observed following epicardial application of fibrin glue at the injection site (37.5±8.2%). PCR revealed a significant increase in 3 week cell engraftment in the fibrin glue animals (22.1±18.6% vs 5.3±3.1%, for fibrin glue and PBS respectively). Conclusions In vivo PET permits accurate measurement of CDC retention early after intramyocardial delivery. Sealing injection sites with fibrin glue or lowering ventricular rate by adenosine may be clinically translatable methods for improving stem cell engraftment in a beating heart.

Discussion

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Cite This Study

Terrovitis et al. (2009) studied Myocardial infarction (permanent left anterior descending coronary artery ligation in rats) (n=85). Intramyocardial 18FDG-labeled cardiac-derived stem cells (CDCs) with epicardial fibrin glue, intravenous adenosine, cardiac arrest, or 2,3-butanedione-2-monoxime vs. Intramyocardial 18FDG-labeled CDCs suspended in plain PBS was evaluated on Acute myocardial cell retention at 1 hour post-injection quantified by in vivo 18FDG PET (p=<0.01). Sealing injection sites with fibrin glue or administering adenosine doubled acute myocardial CDC retention by PET (37.5% and 35.4% vs 17.8% in PBS, p<0.01 and p<0.05).

synapsesocial.com/papers/6ae06bbcff772c0832a0ad67 https://doi.org/10.1016/j.jacc.2009.04.097

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Noninvasive Quantification and Optimization of Acute Cell Retention by In Vivo Positron Emission Tomography After Intramyocardial Cardiac-Derived Stem Cell Delivery

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Noninvasive Quantification and Optimization of Acute Cell Retention by In Vivo Positron Emission Tomography After Intramyocardial Cardiac-Derived Stem Cell Delivery

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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