Shock-Wave Preconditioning Boosts Cell Therapy for Chronic Heart Failure

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A novel method of applying high-dose ultrasound, or shock-wave therapy, prior to administration of bone marrow stem cells in patients with postinfarction heart failure improves left ventricular ejection fraction (LVEF) while reducing major adverse clinical events (MACE), according to a study in the April 17, 2013, issue of the Journal of the American Medical Association. Shock-wave treatment appears to create a kind of ‘homing signal’ to tell the injected cells where to go to be most effective.

The findings were previously presented in January 2012 at the Seventh International Conference on Cell Therapy for Cardiovascular Disease in New York, NY.

For the double-blind CELLWAVE trial, investigators led by Andreas M. Zeiher, MD, of Goethe University (Frankfurt, Germany), enrolled 103 patients with stable advanced chronic heart failure at an average of 6 years after MI.

Patients were randomized in a 2:2:1 ratio to low-dose shock waves (0.014 J/mm²; n = 42), high-dose shock waves (0.051 J/mm²; n = 40), or a sham procedure (n = 21). All therapies were targeted to the left ventricular anterior wall. The following day, after bone marrow aspiration, patients in the 2 shock wave-treated groups were randomized to intracoronary administration of autologous bone marrow stem cells (low-dose shock wave n = 22; high-dose shock wave n = 21) or placebo; the sham group also received bone marrow therapy.

‘Modest’ Improvement in LVEF

At 4 months, the primary endpoint of improvement in LVEF, which was assessed by combining both shock-wave therapy doses, was greater when patients received additional stem cells rather than placebo infusion. Likewise, regional wall thickening improved in conjunction with cell therapy (table 1).

Table 1. Primary and Secondary Endpoints at 4 Months

Further analyses in a prespecified subgroup of patients with baseline LVEF ≤ 40% revealed a dose-response effect (P = 0.03 for trend) on LVEF from low-dose to high-dose shock-wave pretreatment followed by cell therapy.

In 38 patients who underwent MRI assessment, wall thickening of infarcted segments improved more in patients receiving shock-wave treatment with cell therapy (11.9%) rather than placebo infusion (8.9%) or placebo shock wave procedure plus cell therapy (7.0%; P for trend = 0.01). Changes in regional wall thickening were paralleled by a decrease (P = 0.001 for trend) in global infarct size of 3.4% as measured by late enhancement volume in the shock-wave plus cell therapy group. This translated into a relative 10% smaller infarct size at 4 months in that group.

Patients receiving low-dose shock wave plus cell therapy showed a modest improvement in

symptomatic status (absolute change in NYHA class, -0.3), while those receiving high-dose shock wave plus cell therapy demonstrated a greater reduction in NYHA class (absolute change, -0.4), driven by reductions in NYHA class III and corresponding increases in NYHA class I. Serial assessment of NT-proBNP also showed reductions in the shock-wave plus cell therapy group from 1,384 pg/mL at baseline to 1,095 pg/mL at 4 months (P = 0.04).

The overall rate of MACE—including death, rehospitalization for worsening heart failure, recurrent MI, ventricular tachycardia, revascularization, and stroke—was lower in patients given shock wave plus cell therapy compared with either shock wave/placebo infusion or placebo shock wave procedure/cell therapy (HR 0.58; 95% CI 0.40-0.85; P = 0.02). In addition, the observed improvements in contractile left ventricular function and heart failure symptoms were paralleled by a decrease in the overall frequency of individual clinical endpoints.

Shock Waves Provide Guidance for Cells

According to the investigators, preclinical studies suggest that shock wave-induced local up-regulation of chemoattractants such as stromal cell-derived factor 1 (SDF-1) enhances the homing ability of applied cells, which translates into improved neovascularization of chronically ischemic tissue.

“Preconditioning the target tissue by shock wave offers a novel approach to redirect intra-arterially applied cells to the region of interest,” they write, adding that the results show a “significant, albeit modest increase in LVEF attributable to improved wall thickening in the shock wave-treated region.” Importantly, they add, the homogenous response among patients with the most severely impaired LVEF suggests “that target-region preconditioning reduces the heterogeneity in individual responses to intracoronary infusion of [bone marrow stem cells].”

However, the authors caution that the beneficial effects, particularly with regard to clinical outcome, require confirmation in larger trials.

A Step in the Right Direction

“The signals that help to recruit and activate cells involved in myocardial repair are high after acute injury and low or nonexistent in the chronic state,” said Warren Sherman, MD, of Columbia University Medical Center (New York, NY), in an e-mail communication with TCTMD. “Therefore, any means by which such signals are augmented may promote repair, even if long after an MI.”

Dr. Sherman said while the research is a step in the right direction for regenerative therapies, proving the utility of shock-wave mediated cell therapy will require “pivotal studies that demonstrate meaningful clinical benefits as measured by survival and freedom from the adverse consequences of congestive heart failure.”

In a telephone interview with TCTMD, Andre Terzic, MD, PhD, of the Mayo Clinic (Rochester, MN), commented that “this is where this whole area of regenerative therapy is going right now. We are seeing an expanding area of third-generation stem-cell attempts like this in a variety of cardiovascular settings. What has been typically not very robust across these studies is the ultimate efficacy of such treatments.”

Dr. Terzic said conditioning the failing myocardium to accept bone marrow-derived mononuclear cells creates an interface between the injected cells and the heart itself such that “the heart is an active participant in the ultimate outcome.”

“Clearly this concept needs to be further explored,” Dr. Terzic continued. “We are going beyond randomly injecting cells and seeing where they go and instead working toward this second-generation regenerative therapy where we focus on either upgrading the cells themselves or making sure the tissue is enhanced so it can accept them better.”

Study Details

Shock wave treatment was administered under 2-dimensional echocardiographic guidance by a custom-built shock wave generator (Biotripter, Dornier Med Tech Systems, Munich, Germany).

 

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Source:
Assmus B, Walter DH, Seeger FH, et al. Effect of shock wave–facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: The CELLWAVE randomized clinical trial. JAMA 2013;309:1622-1631.

 

• Dr. Zeiher reports serving as a consultant to Baxter Healthcare, Capricor, and Sanofi-Aventis; receiving lecture fees from AstraZeneca, Bayer, Berlin Chemie, and Orbus Neich; and holding patents or patents pending from Siemens Healthcare.
• Drs. Terzic and Sherman report no relevant conflicts of interest.

 

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