Abstract 12573: Induced Pluripotent Stem Cells Treatment Prevent Heart Failure and Ventricular Dyssynchrony in Genetic Non-ischemic Cardiomyopathy
Introduction: Derived by nuclear reprogramming of somatic tissue, induced pluripotent stem (iPS) cells repair ischemic heart injury. The impact of this emerging platform in the treatment of non-ischemic dilated cardiomyopathy (DCM) is unknown.
Hypothesis: iPS transplantation rescues dyssynchronous ventricular contraction, normalizing global and regional myocardial structure and function in DCM-associated heart failure.
Methods: Salient features of the human DCM1O syndrome associated with mutations in cardioprotective ATP-sensitive K+ (KATP) channels were recapitulated in KATP channel-knockout mice under hemodynamic stress imposed by transverse aortic constriction (TAC). iPS were engineered from fibroblasts transduced with human stemness factors OCT3/4, SOX2, KLF4, and c-MYC. At 2 weeks post-TAC, cardiomyopathic animals (n=30) were randomized into cohorts without [iPS(-)] and with iPS treatment [200,000 cells delivered by epicardial injection, iPS(+)], and followed prospectively in blinded fashion, by M-mode/B-mode/speckle-tracking echocardiography, MRI, hemodynamics, electrophysiology, and pathology.
Results: At 100 days post-TAC, untreated KATP channel-deficient hearts developed cardiomegaly, regional and global left ventricular systolic dysfunction, fulminant congestive heart failure and death. Although indistinguishable at randomization, iPS-treated hearts demonstrated improved cardiac contractility [left ventricular ejection fraction: 54.9±5.0% in iPS(+) versus 20.2±3.3% in iPS(-), P<0.001], systolic/diastolic hemodynamics, and were rescued from intra-ventricular dyssynchrony and progressive remodeling. iPS cell therapy normalized sarcomeric, mitochondrial, and gap junction organization within remuscularized hearts. Exercise capacity, lung congestion, maximal oxygen consumption, arterial oxygen saturation, and survivorship were all improved in the iPS-treated cohort, which was free of adverse effects on follow-up.
Conclusions: iPS-based intervention prevented end-stage heart failure and dyssynchrony in the setting of KATP channelopathy, providing preclinical evidence for the benefit of bioengineered pluripotent stem cells in heritable, non-ischemic chronic cardiomyopathy.
- © 2010 by American Heart Association, Inc.