In sum, enhanced cardiac GRK2 dosage in pathological conditions is expected to simultaneously alter key pathways controlling cardiac physiopathology, including βAR and GPCR signaling, mitochondrial function, cardiac insulin signaling, and also metabolic and survival cascades or NO bioavailability, ultimately contributing to altered contractility, metabolic and energetic derangement, pathological gene expression reprogramming, maladaptive myocardial remodeling, and progression to heart failure. The gene discussed is GRK2; the disease is heart failure.