Learning from failure: congestive heart failure in the postgenomic age

Abstract

The prognosis of heart failure is worse than that of most cancers, but new therapeutic interventions using stem and other cell-based therapies are succeeding in the fight against it, and old drugs, with new twists, are making a comeback. Genetically engineered animal models are driving insights into the molecular mechanisms that cause hearts to fail, accelerating drug discoveries, and inspiring cell-based therapeutic interventions for both acquired and inheritable cardiac diseases.

Figure 1

A partial wiring diagram of biological circuits for heart failure. Impaired pump function after myocyte death from myocardial infarction or abnormal loading conditions such as found in hypertension (white) activate a biomechanical stress–dependent signaling cascade (purple). The responsible targets of altered signal transduction cascades in heart failure include transcription factors, coactivators, and corepressors for cardiac gene expression (green) as well as the effector mechanisms like calcium cycling, metabolism, growth, and apoptosis (yellow) that culminate in ventricular dysfunction (orange) and secondary neurohumoral responses (gray) such as adrenergic drive and intramyocardial growth factors (not shown). Inherited mutations for cardiomyopathy (blue) affect proteins at many of these points and are thought to engage a similar cascade of events in order to elicit the full myopathic phenotype. Cell-based therapies (red), although often envisioned working chiefly or wholly by replacing dead myocytes, probably improve ventricular performance through a combination of mechanisms, including angiogenesis, paracrine signals for myocyte protection, and conceivably augmenting host self-repair.