A review. Heart failure (HF) is one of the main causes of morbidity and mortality in the developed world. The prognosis of a patient with chronic NYHA (New York Heart Association) class IV heart failure is bleaker than for a patient with any type of malignancy, except carcinomas of the lung and pancreas; a defining characteristic of the disease is impaired ventricular function, which causes inadequate systemic blood flow, and the body compensates with changes, such as cardiac hypertrophy, increased sympathetic activity and increased activation of the renin-angiotensin system. Another characteristic of HF is systolic dysfunction, which involves reduced left ventricle contractility and a lowered ejection fraction. There are several genetic strategies to modify the underlying disease processes. These include protecting the myocardium by enhanced antioxidant gene expression, the rescue of failing myocardium by enhanced proangiogenic gene expression, and the recovery of contractile function by β-AR signaling; gene delivery interventions have reduced diastolic calcium levels in the cytosol by overexpressing cardiac Ca2+ ATPase of the sarcoplasmic reticulum (SERCA2a), increasing the phospholamban mutated proteins, reducing the endogenous phospholamban and increasing the protein phosphatase-1 inhibitor-1 activity. As myocardium remodeling and the associated hormonal regulation happens over a longer time, meaningful clin. conclusions drawn from βARK overexpression were limited. Koch and colleagues optimized the AAV-based delivery to the myocardium to provide stable, longterm transgene expression. This allowed contractile function changes and neurohormonal signaling normalization to be examined over the clin. relevant time period of 3 mo.