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Posts Tagged ‘CPC’


Intracoronary Transplantation of Progenitor Cells after Acute MI

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Transcoronary Transplantation of Progenitor Cells after Myocardial Infarction

Birgit Assmus, M.D., Jörg Honold, M.D., Volker Schächinger, M.D., Martina B. Britten, M.D., Ulrich Fischer-Rasokat, M.D., et al.
From the Division of Cardiology and Mo­lecular Cardiology, Department of Medi­cine III (B.A., J.H., V.S., M.B.B., U.F.-R., R.L., C.T., K.P., S.D., A.M.Z.), Division of He­matology, Department of Medicine II (H.M.), and the Department of Diagnos­tic and Interventional Radiology (N.D.A.), Johann Wolfgang Goethe University; and the Institute for Transfusion Medicine and Immunohematology, Red Cross Blood Donor Service, Baden–Württem-berg–Hessen (T.T.) — both in Frankfurt, Germany.

N Engl J Med 2006;355:1222-32.

Background

Pilot studies suggest that intracoronary transplantation of progenitor cells derived from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular function after acute myocardial infarction. The effects of cell transplantation in patients with healed myocardial infarction are unknown.

METHODS

After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled crossover study, 75 patients with stable ischemic heart disease who had had a myo­cardial infarction at least 3 months previously to receive either no cell infusion (23 patients) or infusion of CPC (24 patients) or BMC (28 patients) into the patent coro­nary artery supplying the most dyskinetic left ventricular area. The patients in the control group were

  • subsequently randomly assigned to receive CPC or BMC, and
  • the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3 months’ follow-up.

RESULTS

The absolute change in left ventricular ejection fraction was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (−0.4 percentage point, P = 0.003) or no infusion (−1.2 percentage points, P<0.001). The increase in global cardiac function was related to significantly

  • en­hanced regional contractility in the area targeted by intracoronary infusion of BMC.

The crossover phase of the study revealed that intracoronary infusion of BMC was associated with a significant increase in global and regional left ventricular func­tion, regardless of whether patients crossed over from control to BMC or from CPC to BMC.

CONCLUSIONS

Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of BMC is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months. (ClinicalTrials.gov number, NCT00289822.)

Introduction

HRONIC HEART FAILURE IS COMMON, and its prevalence continues to increase.1 Ischemic heart disease is the principal cause of heart failure.2 Although myocardial salvage due to early reperfusion therapy has significantly re­duced early mortality rates,3

  • postinfarction heart failure resulting from ventricular remodeling re­mains a problem.4

One possible approach to re­versing postinfarction heart failure is

  • enhance­ment of the regeneration of cardiac myocytes as well as
  • stimulation of neovascularization within the infarcted area.

Initial clinical pilot studies have suggested that

  • intracoronary infusion of pro­genitor cells is feasible and may
  • beneficially af­fect postinfarction remodeling processes in pa­tients with acute myocardial infarction.5-9

However, it is currently unknown whether such a treatment strategy may also be associated with

  • improvements in cardiac function in patients with persistent left ventricular dysfunction due to healed myocardial infarction with established scar formation.

Therefore, in the prospective TOPCARE-CHD (Transplantation of Progenitor Cells and Recovery of LV [Left Ventricular] Function in Patients with Chronic Ischemic Heart Disease) trial, we inves­tigated

  • whether intracoronary infusion of pro­genitor cells into the infarct-related artery at least 3 months after myocardial infarction improves global and regional left ventricular function.

Patient Outcome Criteria

The primary end point of the study was the absolute change in global left ventricular ejection fraction (LVEF) as measured by quantitative left ventricular angiography 3 months after cell infu­sion. Secondary end points included quantitative variables relating to the regional left ventricular function of the target area, as well as left ven­tricular volumes derived from serial left ventric­ular angiograms. In addition, functional status was assessed by NYHA classification. Finally, event-free survival was defined as freedom from death, myocardial infarction, stroke, or rehospi­talization for worsening heart failure. Causes of rehospitalization during follow-up were verified by review of the discharge letters or charts of hospital stays.

DETECTION OF VIABLE MYOCARDIUM

All patients underwent low-dose dobutamine stress echocardiography, combined thallium sin­gle-photon-emission computed tomography and [18F]fluorodeoxyglucose positron-emission tomog­raphy, or both, as previously described.6 It was pos­sible to analyze regional left ventricular viability in 80 patients (87%).

RESULTS

BASELINE CHARACTERISTICS OF THE PATIENTS

A total of 92 patients were enrolled in the study. Of these, 35 patients received BMC as their ini­tial treatment (in phases 1 and 2 of the trial), 34 patients received CPC (in phases 1 and 2), and 23 patients received no intracoronary cell infu­sion (in phase 2, as the control group). Table 1 illustrates that the three groups of patients were well matched.

EFFECTS OF PROGENITOR-CELL INFUSION

Quantitative Characteristics of Left Ventricular Function

Patients with an adverse clinical event (six), sub­total stenosis of the target vessel at follow-up (three), an intraventricular thrombus precluding performance of left ventricular angiography (one), or atrial flutter or fibrillation at follow-up (one) were excluded from the exploratory analysis. In addition, of the 81 eligible patients, left ventricu­lar angiograms could not be quantitatively ana­lyzed in 4 because of inadequate contrast opaci-fication, in 1 because of ventricular extrasystoles, and in 4 because of the patients’ refusal to un­dergo invasive follow-up. Thus, a total of 72 of 81 serial paired left ventricular angiograms were available for quantitative analysis (28 in the BMC group, 26 in the CPC group, and 18 in the control group).

Table 2 summarizes the angiographic charac­teristics of the 75 patients included in the ran­domized phase of the study. At baseline, the three groups did not differ with respect to global LVEF, the extent or magnitude of regional left ventricu­lar dysfunction, left ventricular volumes, or stroke volumes.

The absolute change in global LVEF from base­line to 3 months did significantly differ among the three groups of patients. Patients receiving BMC had a significantly larger change in LVEF than patients receiving CPC (P = 0.003) and those in the control group (P<0.001). Similar results were ob­tained when patients from the first two phases of the study (the pilot phase and the randomized phase) were pooled. The results did not differ when patients without evidence of viable myo­cardium before inclusion were analyzed sepa­rately. The change in LVEF was −0.3±3.4 percent­age points in the control group (9 patients), +0.4±3.0 percentage points in the CPC group (18 patients), and +3.7±4.0 percentage points in the BMC group (18 patients) (P = 0.02 for the com­parison with the control group and P = 0.02 for the comparison with the CPC group).

In the subgroup of 35 patients who underwent serial assessment of left ventricular function by MRI, MRI-derived global LVEF increased signifi­cantly, by 4.8±6.0% (P = 0.03) among those receiv­ing BMC (11 patients) and by 2.8±5.2% (P = 0.02) among those receiving CPC (20 patients), where­as no change was observed in 4 control patients (P = 0.14). Thus, MRI-derived assessment of left ventricular function further corroborated the re­sults obtained from the total patient population.

Analysis of regional left ventricular function revealed that BMC treatment significantly in­creased contractility in the center of the left ven­tricular target area (Table 2). Likewise, MRI-derived regional analysis of left ventricular function re­vealed that the number of hypocontractile seg­ments was significantly reduced, from 10.1±3.6 to 8.7±3.6 segments (P = 0.02), and the number of normocontractile segments significantly in­creased, from 3.8±4.5 to 5.4±4.6 segments (P = 0.01), in the BMC group, whereas no significant changes were observed in the CPC group. MRI-derived infarct size, as measured by late enhance­ment volume normalized to left ventricular mass, remained constant both in the CPC group (25± 18% at baseline and 23±14% at 3 months,13 patients) and in the BMC group (20±10% at both time points, 9 patients). Thus, taken together, the data suggest that intracoronary infusion of BMC is associated with significant improvements in global and regional left ventricular contractile function among patients with persistent left ven­tricular dysfunction due to prior myocardial in­farction.

To identify independent predictors of improved global LVEF, a stepwise multivariate regression analysis was performed; it included classic deter­minants of LVEF as well as various baseline characteristics of the three groups (Table 3). The multivariate analysis identified the type of pro­genitor cell infused and the baseline stroke vol­ume as the only statistically significant indepen­dent predictors of LVEF recovery.

Functional Status

The functional status of the patients, as assessed by NYHA classification, improved significantly in the BMC group (from 2.23±0.6 to 1.97±0.7, P = 0.005). It did not improve significantly either in the CPC group (class, 2.16±0.8 at baseline and 1.93±0.8 at 3 months; P = 0.13) or in the control group (class, 1.91±0.7 and 2.09±0.9, respectively; P = 0.27).

RANDOMIZED CROSSOVER PHASE

Of the 24 patients who initially were randomly assigned to CPC infusion, 21 received BMC at the time of their first follow-up examination. Likewise, of the 28 patients who initially were randomly assigned to BMC infusion,

  • 24 received CPC after 3 months.

Of the 23 patients of the control group, 10 patients received CPC and 11 received BMC at their reexamination at 3 months (Fig. 1). As illustrated in Figure 2, regardless of whether patients received BMC as initial treatment, as crossover treatment after CPC infusion, or as crossover treatment after no cell infusion,

  • glob­al LVEF increased significantly after infusion of BMC. In contrast,
  • CPC treatment did not significantly alter LVEF when given either before or after BMC.

Thus, the intrapatient comparison of the dif­ferent treatment strategies not only documents the superiority of intracoronary infusion of BMC over the infusion of CPC for improving global left ventricular function, but also corroborates our findings in the analysis of data according to initial treatment assignment. The

  • preserved im­provement in cardiac function observed among patients who initially received BMC treatment and
  • then crossed over to CPC treatment demon­strates that the initially achieved differences in cardiac function persisted for at least 6 months after intracoronary infusion of BMC.
 Table 1. Baseline Characteristics of the Patients.* (not copied)  

Table 2. Quantitative Variables Pertaining to Left Ventricular Function, as Assessed by Left Ventricular Angiography.*

copy protected

Figure 2. Absolute Change in Quantitative Global Left Ventricular Ejection Fraction (LVEF) during the Crossover Phase of the Trial.

Data at 3 and 6 months are shown for all patients crossing over from BMC to CPC infusion (18 patients), from CPC to BMC infusion
(18 patients), and from no cell infusion to either CPC infusion (10 patients) or BMC infusion (11 patients). I bars represent standard
errors.

Table 3. Stepwise Linear Regression Analysis for Predictors of Improvement in Global Left Ventricular Ejection Fraction.*

Variable Nonstandardized Coefficient B

95% CI for B

P Value

Treatment group

1.49

0.53 to 2.46

0.003
Baseline stroke volume

−0.13

−0.22 to –0.05

0.002
No. of cardiovascular risk factors 0.76
Time since most recent MI 0.48
Concomitant PCI 0.60
Age 0.82
Baseline ejection fraction 0.72
Baseline end-diastolic volume 0.88

* Values are shown only for significant differences. MI denotes myocardial infarc­tion, and PCI percutaneous coronary intervention. For the overall model, the ad­justed R2 was 0.29; P<0.001 by analysis of variance.

 

DISCUSSION

Intrapatient comparison in the crossover phase of the trial rules out the possibility that differences in the patient populations studied may have affected outcomes. However, the mechanisms involved in mediating improved contractile function after intracoronary progenitor-cell infusion are not well understood.

Experimentally, although there is no definitive proof that cardiac myocytes may be regenerated, BMC were shown to contribute to functional re­covery of left ventricular contraction when in­jected into freshly infarcted hearts,13-15 whereas CPC profoundly stimulated ischemia-induced neovascularization.16,17 Both cell types were shown to prevent cardiomyocyte apoptosis and reduce the development of myocardial fibrosis and there­by improve cardiac function after acute myocar­dial infarction.18,19 Indeed, in our TOPCARE-AMI (Transplantation of Progenitor Cells and Regen­eration Enhancement in Acute Myocardial Infarc­tion) studies,6,7,9 intracoronary infusion of CPC was associated with functional improvements similar to those found with the use of BMC im­mediately after myocardial infarction. In the cur­rent study, however, which involved patients who had had a myocardial infarction at least 3 months before therapy,

  • transcoronary adminis­tration of CPC was significantly inferior to administration of BMC in altering global left ven­tricular function.

CPC obtained from patients with chronic ischemic heart disease show pro­found functional impairments,20,21 which might limit their recruitment, after intracoronary infu­sion, into chronically reperfused scar tissue many months or years after myocardial infarction. Thus, additional studies in which larger numbers of functionally enhanced CPC are used will be re­quired to increase the response to intracoronary infusion of CPC.

The magnitude of the improvement after in-tracoronary infusion of BMC, with absolute increases in global LVEF of approximately 2.9 percentage points according to left ventricular angiography and 4.8 percentage points accord­ing to MRI, was modest. However, it should be noted that the improvement in LVEF occurred in the setting of full conventional pharmacologic treatment: more than 90% of the patients were receiving beta-blocker and angiotensin-convert-ing–enzyme inhibitor treatment. Moreover, results from trials of contemporary reperfusion for the treatment of acute myocardial infarction, which is regarded as the most effective treatment strat­egy for improving left ventricular contractile per­formance after ischemic injury, have reported in­creases in global LVEF of 2.8% (in the CADILLAC [Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications] trial) and 4.1% (in the ADMIRAL [Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Fol­low-up] trial).22,23

The number of patients, as well as the dura­tion of follow-up, is not sufficient to address the question of whether the moderate improvement in LVEF associated with one-time intracoronary BMC infusion is associated with reduced mortal­ity and morbidity among patients with heart fail­ure secondary to previous myocardial infarction. We conclude that intracoronary infusion of BMC is associated with persistent improvements in regional and global left ventricular function and improved functional status among patients who have had a myocardial infarction at least 3 months previously. Given the reasonable short-term safety profile of this therapeutic ap­proach, studies on a larger scale are warranted to examine its potential effects on morbidity and mortality among patients with postinfarction heart failure.

REFERENCES (1-8/23)

  1. 2001 Heart and stroke statistical up­date. Dallas: American Heart Association, 2000.
  2. Braunwald E. Cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med 1997;337:1360-9.
  3. Lange RA, Hillis LD. Reperfusion ther­apy in acute myocardial infarction. N Engl J Med 2002;346:954-5.
  4. Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000;101:2981-8.
  5. Strauer BE, Brehm M, Zeus T, et al. Re­pair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circula­tion 2002;106:1913-8.
  6. Assmus B, Schachinger V, Teupe C, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myo­cardial Infarction (TOPCARE-AMI). Circu­lation 2002;106:3009-17.
  7. Britten MB, Abolmaali ND, Assmus B, et al. Infarct remodeling after intra-coronary progenitor cell treatment in pa­tients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003;108: 2212-8.
  8. Wollert KC, Meyer GP, Lotz J, et al. In-tracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141-8.

 

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