Gene Therapy to Treat Cardiovascular Disease

C oronary artery disease, heart failure, and cardiac arrhythmias are major causes of morbidity and mortality in the United States. The overall death rate for all cardiovascular diseases was 236.1 per 100 000 persons, accounting for 1 of every 3 deaths in America. Cardiac diseases can affect every age group, but prevalence is seen in patients 65 or older. For instance, heart failure incidence approaches 1 in 100 older Americans. As of 2009, cardiac arrest accounted for ≥14% of all deaths in the United States. Pharmacologic drugs and device therapies have multiple limitations, and there exists an unmet need for improved clinical outcomes without side effects. Interventional procedures including angioplasty and ablation have improved the prognosis for patients with ischemia and arrhythmias, respectively. However, large subgroups of patients are still left with significant morbidity despite those therapies. This limitation in currently available therapies has prompted extensive investigation into new treatment modalities. Sequencing information from the human genome and the development of gene transfer vectors and delivery systems have given researchers the tools to target specific genes and pathways that play a role in cardiovascular diseases. Early-stage clinical studies have demonstrated promising signs of efficacy in some trials, with few side effects in all trials. Preclinical studies suggest that myocardial gene transfer can improve angiogenesis with vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF), increase myocardial contractility and reduced arrhythmia vulnerability with sarcoplasmic reticulum Ca adenosine triphosphatase, induce cardiac repair with stromal-derived factor-1 (SDF-1), control heart rate in atrial fibrillation with an inhibitory G protein a subunit, and reduce atrial fibrillation and ventricular tachycardia vulnerability with connexins 40 and 43, the skeletal muscle sodium channel SCN4a, or a dominant-negative mutation of the rapid component of the delayed rectifier potassium channel, KCNH2-G628S. The field of myocardial genetic manipulation is vast because of complex and multifaceted disease mechanisms. Many different gene products can be targeted to ameliorate clinical phenotypes, and there exist several delivery vectors for use in the clinic. This review focuses on 3 main cardiac diseases that are currently being evaluated for therapeutic benefit of gene therapy: coronary artery disease, heart failure, and arrhythmias. Status of preclinical or clinical trial progress will be noted as well as a description of the genes being manipulated.