Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction)

Abstract

Objectives: This study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial.

Background: Cardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown.

Methods: Autologous CDCs (12.5 to 25 × 10(6)) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-MI). Eight patients were followed as routine-care control patients.

Results: In 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-MI responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDC-treated subjects were consistent with the natural relationship between scar size and ejection fraction post-MI.

Conclusions: Intracoronary administration of autologous CDCs did not raise significant safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year post-treatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials. (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction [CADUCEUS]; NCT00893360).

Keywords: CDC; CK-MB; CT; DSMB; Data and Safety Monitoring Board; EDV; EF; ESV; Ecc; FWHM; ICD; LV; LVEF; MI; MRI; NYHA; New York Heart Association; SAE; TnI; Vo(2); cardiosphere-derived cell; cardiosphere-derived cells; computed tomography; creatine kinase-myocardial band; ejection fraction; end-diastolic volume; end-systolic volume; full width at half maximum; implantable cardioverter-defibrillator; left ventricular; left ventricular ejection fraction; magnetic resonance imaging; myocardial infarction; myocardial regeneration; oxygen consumption; serious adverse event(s); systolic circumferential strain; troponin I.

Figure 1. CDC Manufacturing and Phenotypic Characterization

(A) Biopsy specimens are minced into ~1 mm³ explants. Explants are plated and spontaneously yield outgrowth cells (left). Outgrowth cells are harvested and plated in suspension culture, where they self-assemble into cardiospheres (middle). Cardiospheres are subsequently replated in fibronectin-coated dishes to yield CDCs (right). (B) Representative flow cytometry histograms for CD105 and CD45. (C) Antigenic profile of CDCs by flow cytometry. CDC = cardiosphere-derived cell; aSMA = α-smooth muscle actin; DDR2 = discoidin domain-containing receptor 2.

Figure 2. Autologous CDCs Decrease Scar Size, Decrease Scar Mass, Increase Viable Myocardium, and Improve Regional Function of Infarcted Myocardium

(A) Changes in scar size from baseline to 1 year. (B) Changes in scar mass and viable mass from baseline 1 year. (C) Correlation between the change in scar mass and the change in viable mass in individual control and CDC-treated subjects from baseline to 1 year (blue line of best fit is derived only from the CDC-treated patients). (D) Regional strain in infarcted segments at 1 year in control patients and CDC-treated patients. (E) Systolic thickening in infarcted segments at 1 year in control and CDC-treated patients. (F) End-systolic thickness in infarcted segments at 1 year in controls and CDC-treated subjects. CDC = cardiosphere-derived cell; Ecc = systolic circumferential strain; ES = end-systolic.

Figure 3. Comprehensive Magnetic Resonance Imaging Analysis of Regeneration

(A) Representative matched, delayed contrast-enhanced magnetic resonance images and their corresponding cine short-axis images (at end-diastole [ED] and end-systole [ES]) at baseline and 1 year (see videos of the cine acquisitions provided in the Online Appendix). In the pseudocolored, delayed contrast-enhanced images, infarct scar tissue, as determined by the full width half maximum method, appears pink. Each cardiac slice was divided into 6 segments (using the right ventricle insertion as a reference point). Infarcted segments were visually identified from delayed contrast-enhanced images. Scar size (percentage of infarcted tissue per segment) and systolic thickening were calculated for each individual infarcted segment at baseline and 1 year. Endocardial (red) and epicardial (green) contours of the left ventricle are shown. In the CDC-treated patient (top row), scar decreased, viable mass increased and regional systolic function improved over the period of 1 year in the treated infarcted segments (highlighted by arrows). In contrast, no major changes in scar mass, viable myocardial mass, or regional systolic function were observed in the control patient (bottom row). (B) Scatterplots of the changes in the percentage of infarcted tissue and the changes in systolic thickening for every infarcted segment of treated and control patients. ED = end-diastole; other abbreviations as in Figures 1 and 2.

Figure 4. Global Function and Left Ventricular Volumes

(A) Scatterplot showing the natural relationship between scar size and left ventricular ejection fraction ~5 months post-myocardial infarction (circles). Each cross symbol represents the mean values (at the intersection of the vertical and horizontal bars [obtained from all patients with magnetic resonance imaging measurements]), whereas the width of each bar equals ±SEM of scar size and left ventricular ejection fraction of CADUCEUS patients at baseline, 6 months, and 1 year; the crosses are superimposed onto the scatterplot showing prior data from post-myocardial infarction patients with variable scar sizes. The changes in left ventricular ejection fraction in CDC-treated subjects are consistent with the natural relationship between scar size and ejection fraction in convalescent myocardial infarction, whereas the changes in left ventricular ejection fraction in controls fall within the margins of variability. (B) Changes in end-diastolic volume from baseline to 1 year. (C) Changes in end-systolic volume from baseline to 1 year. CDCs = cardiosphere-derived cells; EDV = end-diastolic volume; EF = ejection fraction; ESV = end-systolic volume; LV = left ventricle.

Figure 5. Predictors of Efficacy

(A) Correlation between the change in scar size (from baseline to 1 year) and baseline scar size. (B) Correlation between the change in scar size (from baseline to 1 year) and baseline left ventricular ejection fraction. (C) Correlation between the change in scar size (from baseline to 1 year) and time from MI to infusion of CDCs. (D) Changes in scar size from baseline to in year in CDC-treated patients with and without history of temporally remote MI. MI = myocardial infarction; other abbreviations as in Figures 1 and 4.