Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling

Abstract

Rationale: Transcatheter, intramyocardial injections of bone marrow-derived cell therapy produces reverse remodeling in large animal models of ischemic cardiomyopathy.

Objective: We used cardiac MRI (CMR) in patients with left ventricular (LV) dysfunction related to remote myocardial infarction (MI) to test the hypothesis that bone marrow progenitor cell injection causes functional recovery of scarred myocardium and reverse remodeling.

Methods and results: Eight patients (aged 57.2±13.3 years) received transendocardial, intramyocardial injection of autologous bone marrow progenitor cells (mononuclear or mesenchymal stem cells) in LV scar and border zone. All patients tolerated the procedure with no serious adverse events. CMR at 1 year demonstrated a decrease in end diastolic volume (208.7±20.4 versus 167.4±7.32 mL; P=0.03), a trend toward decreased end systolic volume (142.4±16.5 versus 107.6±7.4 mL; P=0.06), decreased infarct size (P<0.05), and improved regional LV function by peak Eulerian circumferential strain in the treated infarct zone (-8.1±1.0 versus -11.4±1.3; P=0.04). Improvements in regional function were evident at 3 months, whereas the changes in chamber dimensions were not significant until 6 months. Improved regional function in the infarct zone strongly correlated with reduction of end diastolic volume (r(2)=0.69, P=0.04) and end systolic volume (r(2)=0.83, P=0.01).

Conclusions: These data suggest that transcatheter, intramyocardial injections of autologous bone marrow progenitor cells improve regional contractility of a chronic myocardial scar, and these changes predict subsequent reverse remodeling. The findings support the potential clinical benefits of this new treatment strategy and ongoing randomized clinical trials.

Figure 1

CMR changes after bone marrow progenitor cell injections. Cine changes in (A) EDV and (B) ESV show reverse remodeling occurred at 6 months and continued through 1 year. Peak Ecc of tagged tissue images demonstrates improved regional function of the (C) treated infarct zone (IZ). Improved IZ contractility (more negative Ecc indicates greater circumferential contractility) occured by 3 months following cell injection and persisted at 6 and 12 months. (D) Shows reduced delayed enhancement infarct size as a percentage of LV mass. (E) LV mass or (F) EF are unchanged. *p<0.05 for difference between time post-injection and baseline in the repeated measures ANOVA.

Figure 2

Autologous bone marrow progenitor cell injections increase regional function and precede reverse remodeling. Panels A-I depict a patient injected with bone marrow progenitor cells. (A) Baseline lateral wall infarct in delayed enhancement CMR (white arrows), (B) 1 year post-injection infarct, (C) infarct mapped to corresponding segmented tagged CMR image with IZ defined by the presence of enhancing myocardium, neighboring myocardium as BZ, and normal myocardium as RZ (first segment of each map correlated by right ventricle insertion point, white arrow head). Tagged harmonic phase CMR strain maps show (D) significantly depressed regional function by peak Ecc at baseline in IZ (white arrows). Red/white indicates weak contractility (more positive Ecc) and green/blue indicates vigorous contractility (more negative Ecc) in harmonic phase strain maps. At (E) three months after cell injection the IZ contractility has improved (less red/white, more green/blue) and by (F) 12 months is contracting similar to the BZ (mostly green/blue). ESV remains relatively stable between (G) baseline and (H) 3 months; however, at (I) 1 year reverse remodeling is present. Changes in peak Ecc of the IZ had a strong correlation with the changes in (J) EDV and (K) ESV at 12 months compared to baseline (difference in peak Ecc between baseline and 1 year versus difference in normalized EDV and ESV, respectively). (L) Decreases in EDV and ESV strongly correlate with each other indicating parallel decreases in chamber sizes contributes to unchanging EF after bone marrow stem cell injections.

Figure 2

Autologous bone marrow progenitor cell injections increase regional function and precede reverse remodeling. Panels A-I depict a patient injected with bone marrow progenitor cells. (A) Baseline lateral wall infarct in delayed enhancement CMR (white arrows), (B) 1 year post-injection infarct, (C) infarct mapped to corresponding segmented tagged CMR image with IZ defined by the presence of enhancing myocardium, neighboring myocardium as BZ, and normal myocardium as RZ (first segment of each map correlated by right ventricle insertion point, white arrow head). Tagged harmonic phase CMR strain maps show (D) significantly depressed regional function by peak Ecc at baseline in IZ (white arrows). Red/white indicates weak contractility (more positive Ecc) and green/blue indicates vigorous contractility (more negative Ecc) in harmonic phase strain maps. At (E) three months after cell injection the IZ contractility has improved (less red/white, more green/blue) and by (F) 12 months is contracting similar to the BZ (mostly green/blue). ESV remains relatively stable between (G) baseline and (H) 3 months; however, at (I) 1 year reverse remodeling is present. Changes in peak Ecc of the IZ had a strong correlation with the changes in (J) EDV and (K) ESV at 12 months compared to baseline (difference in peak Ecc between baseline and 1 year versus difference in normalized EDV and ESV, respectively). (L) Decreases in EDV and ESV strongly correlate with each other indicating parallel decreases in chamber sizes contributes to unchanging EF after bone marrow stem cell injections.

Figure 2

Autologous bone marrow progenitor cell injections increase regional function and precede reverse remodeling. Panels A-I depict a patient injected with bone marrow progenitor cells. (A) Baseline lateral wall infarct in delayed enhancement CMR (white arrows), (B) 1 year post-injection infarct, (C) infarct mapped to corresponding segmented tagged CMR image with IZ defined by the presence of enhancing myocardium, neighboring myocardium as BZ, and normal myocardium as RZ (first segment of each map correlated by right ventricle insertion point, white arrow head). Tagged harmonic phase CMR strain maps show (D) significantly depressed regional function by peak Ecc at baseline in IZ (white arrows). Red/white indicates weak contractility (more positive Ecc) and green/blue indicates vigorous contractility (more negative Ecc) in harmonic phase strain maps. At (E) three months after cell injection the IZ contractility has improved (less red/white, more green/blue) and by (F) 12 months is contracting similar to the BZ (mostly green/blue). ESV remains relatively stable between (G) baseline and (H) 3 months; however, at (I) 1 year reverse remodeling is present. Changes in peak Ecc of the IZ had a strong correlation with the changes in (J) EDV and (K) ESV at 12 months compared to baseline (difference in peak Ecc between baseline and 1 year versus difference in normalized EDV and ESV, respectively). (L) Decreases in EDV and ESV strongly correlate with each other indicating parallel decreases in chamber sizes contributes to unchanging EF after bone marrow stem cell injections.

Figure 2

Autologous bone marrow progenitor cell injections increase regional function and precede reverse remodeling. Panels A-I depict a patient injected with bone marrow progenitor cells. (A) Baseline lateral wall infarct in delayed enhancement CMR (white arrows), (B) 1 year post-injection infarct, (C) infarct mapped to corresponding segmented tagged CMR image with IZ defined by the presence of enhancing myocardium, neighboring myocardium as BZ, and normal myocardium as RZ (first segment of each map correlated by right ventricle insertion point, white arrow head). Tagged harmonic phase CMR strain maps show (D) significantly depressed regional function by peak Ecc at baseline in IZ (white arrows). Red/white indicates weak contractility (more positive Ecc) and green/blue indicates vigorous contractility (more negative Ecc) in harmonic phase strain maps. At (E) three months after cell injection the IZ contractility has improved (less red/white, more green/blue) and by (F) 12 months is contracting similar to the BZ (mostly green/blue). ESV remains relatively stable between (G) baseline and (H) 3 months; however, at (I) 1 year reverse remodeling is present. Changes in peak Ecc of the IZ had a strong correlation with the changes in (J) EDV and (K) ESV at 12 months compared to baseline (difference in peak Ecc between baseline and 1 year versus difference in normalized EDV and ESV, respectively). (L) Decreases in EDV and ESV strongly correlate with each other indicating parallel decreases in chamber sizes contributes to unchanging EF after bone marrow stem cell injections.

Figure 2

Autologous bone marrow progenitor cell injections increase regional function and precede reverse remodeling. Panels A-I depict a patient injected with bone marrow progenitor cells. (A) Baseline lateral wall infarct in delayed enhancement CMR (white arrows), (B) 1 year post-injection infarct, (C) infarct mapped to corresponding segmented tagged CMR image with IZ defined by the presence of enhancing myocardium, neighboring myocardium as BZ, and normal myocardium as RZ (first segment of each map correlated by right ventricle insertion point, white arrow head). Tagged harmonic phase CMR strain maps show (D) significantly depressed regional function by peak Ecc at baseline in IZ (white arrows). Red/white indicates weak contractility (more positive Ecc) and green/blue indicates vigorous contractility (more negative Ecc) in harmonic phase strain maps. At (E) three months after cell injection the IZ contractility has improved (less red/white, more green/blue) and by (F) 12 months is contracting similar to the BZ (mostly green/blue). ESV remains relatively stable between (G) baseline and (H) 3 months; however, at (I) 1 year reverse remodeling is present. Changes in peak Ecc of the IZ had a strong correlation with the changes in (J) EDV and (K) ESV at 12 months compared to baseline (difference in peak Ecc between baseline and 1 year versus difference in normalized EDV and ESV, respectively). (L) Decreases in EDV and ESV strongly correlate with each other indicating parallel decreases in chamber sizes contributes to unchanging EF after bone marrow stem cell injections.

Figure 2

Autologous bone marrow progenitor cell injections increase regional function and precede reverse remodeling. Panels A-I depict a patient injected with bone marrow progenitor cells. (A) Baseline lateral wall infarct in delayed enhancement CMR (white arrows), (B) 1 year post-injection infarct, (C) infarct mapped to corresponding segmented tagged CMR image with IZ defined by the presence of enhancing myocardium, neighboring myocardium as BZ, and normal myocardium as RZ (first segment of each map correlated by right ventricle insertion point, white arrow head). Tagged harmonic phase CMR strain maps show (D) significantly depressed regional function by peak Ecc at baseline in IZ (white arrows). Red/white indicates weak contractility (more positive Ecc) and green/blue indicates vigorous contractility (more negative Ecc) in harmonic phase strain maps. At (E) three months after cell injection the IZ contractility has improved (less red/white, more green/blue) and by (F) 12 months is contracting similar to the BZ (mostly green/blue). ESV remains relatively stable between (G) baseline and (H) 3 months; however, at (I) 1 year reverse remodeling is present. Changes in peak Ecc of the IZ had a strong correlation with the changes in (J) EDV and (K) ESV at 12 months compared to baseline (difference in peak Ecc between baseline and 1 year versus difference in normalized EDV and ESV, respectively). (L) Decreases in EDV and ESV strongly correlate with each other indicating parallel decreases in chamber sizes contributes to unchanging EF after bone marrow stem cell injections.

Figure 2

Autologous bone marrow progenitor cell injections increase regional function and precede reverse remodeling. Panels A-I depict a patient injected with bone marrow progenitor cells. (A) Baseline lateral wall infarct in delayed enhancement CMR (white arrows), (B) 1 year post-injection infarct, (C) infarct mapped to corresponding segmented tagged CMR image with IZ defined by the presence of enhancing myocardium, neighboring myocardium as BZ, and normal myocardium as RZ (first segment of each map correlated by right ventricle insertion point, white arrow head). Tagged harmonic phase CMR strain maps show (D) significantly depressed regional function by peak Ecc at baseline in IZ (white arrows). Red/white indicates weak contractility (more positive Ecc) and green/blue indicates vigorous contractility (more negative Ecc) in harmonic phase strain maps. At (E) three months after cell injection the IZ contractility has improved (less red/white, more green/blue) and by (F) 12 months is contracting similar to the BZ (mostly green/blue). ESV remains relatively stable between (G) baseline and (H) 3 months; however, at (I) 1 year reverse remodeling is present. Changes in peak Ecc of the IZ had a strong correlation with the changes in (J) EDV and (K) ESV at 12 months compared to baseline (difference in peak Ecc between baseline and 1 year versus difference in normalized EDV and ESV, respectively). (L) Decreases in EDV and ESV strongly correlate with each other indicating parallel decreases in chamber sizes contributes to unchanging EF after bone marrow stem cell injections.

Figure 2

Autologous bone marrow progenitor cell injections increase regional function and precede reverse remodeling. Panels A-I depict a patient injected with bone marrow progenitor cells. (A) Baseline lateral wall infarct in delayed enhancement CMR (white arrows), (B) 1 year post-injection infarct, (C) infarct mapped to corresponding segmented tagged CMR image with IZ defined by the presence of enhancing myocardium, neighboring myocardium as BZ, and normal myocardium as RZ (first segment of each map correlated by right ventricle insertion point, white arrow head). Tagged harmonic phase CMR strain maps show (D) significantly depressed regional function by peak Ecc at baseline in IZ (white arrows). Red/white indicates weak contractility (more positive Ecc) and green/blue indicates vigorous contractility (more negative Ecc) in harmonic phase strain maps. At (E) three months after cell injection the IZ contractility has improved (less red/white, more green/blue) and by (F) 12 months is contracting similar to the BZ (mostly green/blue). ESV remains relatively stable between (G) baseline and (H) 3 months; however, at (I) 1 year reverse remodeling is present. Changes in peak Ecc of the IZ had a strong correlation with the changes in (J) EDV and (K) ESV at 12 months compared to baseline (difference in peak Ecc between baseline and 1 year versus difference in normalized EDV and ESV, respectively). (L) Decreases in EDV and ESV strongly correlate with each other indicating parallel decreases in chamber sizes contributes to unchanging EF after bone marrow stem cell injections.

Figure 2

Autologous bone marrow progenitor cell injections increase regional function and precede reverse remodeling. Panels A-I depict a patient injected with bone marrow progenitor cells. (A) Baseline lateral wall infarct in delayed enhancement CMR (white arrows), (B) 1 year post-injection infarct, (C) infarct mapped to corresponding segmented tagged CMR image with IZ defined by the presence of enhancing myocardium, neighboring myocardium as BZ, and normal myocardium as RZ (first segment of each map correlated by right ventricle insertion point, white arrow head). Tagged harmonic phase CMR strain maps show (D) significantly depressed regional function by peak Ecc at baseline in IZ (white arrows). Red/white indicates weak contractility (more positive Ecc) and green/blue indicates vigorous contractility (more negative Ecc) in harmonic phase strain maps. At (E) three months after cell injection the IZ contractility has improved (less red/white, more green/blue) and by (F) 12 months is contracting similar to the BZ (mostly green/blue). ESV remains relatively stable between (G) baseline and (H) 3 months; however, at (I) 1 year reverse remodeling is present. Changes in peak Ecc of the IZ had a strong correlation with the changes in (J) EDV and (K) ESV at 12 months compared to baseline (difference in peak Ecc between baseline and 1 year versus difference in normalized EDV and ESV, respectively). (L) Decreases in EDV and ESV strongly correlate with each other indicating parallel decreases in chamber sizes contributes to unchanging EF after bone marrow stem cell injections.