Despite improvements in drug and device therapy for heart failure, hospitalization rates and mortality have\nchanged little in the past decade. Randomized clinical trials using gene transfer to improve function of the\nfailing heart are the focus of this review. Four randomized clinical trials of gene transfer in heart failure with\nreduced ejection fraction (HFrEF) have been published. Each enrolled patients with stable symptomatic\nHFrEF and used either intracoronary delivery of a virus vector or endocardial injection of a plasmid. The\ninitial CUPID trial randomized 14 subjects to placebo and 25 subjects to escalating doses of adeno-associated\nvirus type 1 encoding sarcoplasmic reticulum calcium ATPase (AAV1.SERCA2a). AAV1.SERCA2a was well\ntolerated, and the high-dose group met a 6 month composite endpoint. In the subsequent CUPID-2 study, 243\nsubjects received either placebo or the high dose of AAV1.SERCA2a. AAV1.SERCA2a administration, while\nsafe, failed to meet the primary or any secondary endpoints. STOP-HF used plasmid endocardial injection of\nstromal cell-derived factor-1 to promote stem-cell recruitment. In a 93-subject trial of patients with ischemic\netiology heart failure, the primary endpoint (symptoms and 6min walk distance) failed, but subgroup analyses\nshowed improvements in subjects with the lowest ejection fractions. A fourth trial randomized 14\nsubjects to placebo and 42 subjects to escalating doses of adenovirus-5 encoding adenylyl cyclase 6 (Ad5.hAC6).\nThere were no safety concerns, and patients in the two highest dose groups (combined) showed improvements\nin left ventricular function (left ventricular ejection fraction and ââ?¬â??dP/dt). The safety data from four randomized\nclinical trials of gene transfer in patients with symptomatic HFrEF suggest that this approach can be\nconducted with acceptable risk, despite invasive delivery techniques in a high-risk population. Additional\ntrials are necessary before the approach can be endorsed for clinical practice.
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