Gene Transfer Improves Function in Heart Failure, Hospitalizations Reduced

Could gene transfer be the answer to reducing hospitalizations for veterans with heart failure? A new trial by VA researchers suggests that’s a good possibility, with a single intracoronary injection of an adenovirus to transfer the gene that produces the protein adenylyl cyclase 6 (AC6) reducing admission rates by one-third.

By Annette M. Boyle

SAN DIEGO—Heart failure continues to top the list of reasons veterans are admitted to VHA hospitals, despite use of therapies that include angiotensin converting enzyme (ACE) inhibitors, beta-blockers, aldosterone antagonists and implantable cardioverter-defibrillators (ICDs).

Research into gene transfer led by researchers at the VA San Diego Healthcare System could bring those hospitalization rates down sharply by significantly improving heart function.

Better heart function has the potential to reduce mortality rates as well. “Current mortality on optimal therapy for patients with symptomatic heart failure is worse than what is seen in most cancers. Up to 50% of such patients do not survive for five years after symptom onset,” according to lead investigator H. Kirk Hammond, MD, a cardiologist at the VA San Diego.

In a multicenter, phase II trial, the researchers evaluated the results of gene transfer, using a single intracoronary injection of an adenovirus to transfer the gene that produces the protein adenylyl cyclase 6 (AC6) into the heart cells of patients with symptomatic heart failure. AC6 helps convert adenosine triphosphate to cyclic adenosine monophosphate, which is critical to heart function and contributes to calcium handling. In heart failure, AC6 levels are reduced.1  

Researchers reported that patients who received AC6 had one-third the rate of hospitalizations in a year of follow-up, compared to those who received placebo—9.5% vs. 29%. They also had improved left ventricle function. Results of the trial were published in JAMA Cardiology.

The research team randomly assigned 56 patients with symptomatic heart failure and impaired left ventricle function to receive either placebo or one of five dosages of the study product (Ad5.hAC6) plus nitroprusside, which increases the efficiency of gene transfer. Of the participants, 14 received placebo, six received each of the lowest three doses, D1-D3, and 12 received each of the two highest doses, D4 and D5.

Left Ventricular (LV) Pressure Development (+dP/dt), LV Decline (−dP/dt), and Symptom Scores A, LV peak −dP/dt decreased (LV pressure decline more rapid) in D4 + 5 participants (n = 22) compared with placebo participants (n = 14) 4 weeks after treatment. This between-group difference was statistically significant (P < .03). B, There was no between-group difference in LV peak +dP/dt between 14 placebo and 21 D4 + 5 participants (P = .42). C, D4 + 5 participants (baseline, n = 22; 4 weeks, n = 23; 12 weeks, n = 22) had reduced symptoms 12 weeks after randomization (P = .0005); no significant changes were noted in the placebo group (baseline, n = 13; 4 weeks, n = 14; 12 weeks, n = 13) (P = .16). Error bars denote SE. There was no between-group difference in symptom scores between D4 + 5 and placebo at 4 weeks (P = .85) and 12 weeks (P = .24). AC6 indicates adenylyl cyclase 6.

All patients had at least left ventricle ejection fraction of 40% or less, and the mean was 31%. Slightly less than half (48%) of the participants had ischemic heart failure, and 52% had non-ischemic etiology. Initially, the study excluded individuals with anti-Ad5 titers in excess of 1:256, but the resultant very high rate of screen failure led to elimination of that requirement after the lowest dose was tested. The authors pointed out that previous studies had not found a link between high Ad5 titers and gene transfer results.

Dose-Related Effect

“We tested five doses in the initial trial, and there was a dose-related effect, with the highest dose tested providing the best result,” Hammond told U.S. Medicine. “This was achieved with no increase in adverse events compared to patients that received placebo.”

Use of the adenovirus did not increase cardiac or hepatic inflammation, and the gene transfer did not increase rates of tachycardia or implanted cardiac defibrillator events.

Gene transfer increased left ventricular peak pressure decline. It also increased ejection fraction in patients with non-ischemic heart failure. While ischemic and non-ischemic patients receiving the two highest doses (which were the only ones analyzed) and patients receiving placebo showed improvement in left ventricle ejection fraction at four weeks, only the non-ischemic patients showed a notable increase at 12 weeks.

“These data suggest that targeting AD5hAC6 to participants with non-ischemic etiology heart failure would have the most benefit,” the authors wrote. They suggested the difference in response could be related to the effect of ischemia on endothelial function or reduction of viable myocardium, but called for additional research for clarification.

For patients with non-ischemic heart failure, however, the results are quite significant. “AC6 gene transfer increased LV function beyond optimal heart failure therapy through a single administration,” the authors noted.

The improvement in left ventricular peak pressure decline is linked to LV relaxation, the authors noted, raising the question of possible benefits of AC6 gene transfer in heart failure with preserved ejection fraction, a common condition with no treatment that reduces mortality.

No differences were noted between patients receiving the highest doses of the study product and those receiving placebo in right atrial, pulmonary artery wedge or left ventricle end-diastolic pressures.

While the AC6 group had 66% lower relative risk of death, only two patients in the study died, one on placebo and one receiving AC6.

“We do not know whether mortality will be reduced with AC6 gene transfer, because the initial trial was too small,” Hammond explained. “But our hope is that the improved heart function that we saw will translate to improved survival. We saw reduced hospitalization for heart failure in our initial trial, and this, if confirmed in the larger trial, would also be a benefit for patients.”

Hammond and his colleagues will have a chance to see whether gene transfer continues to show promise for improving heart function and reducing mortality in a larger, phase 3 clinical trial set to start shortly. The new trial will enroll up to 750 patients. Half will receive the highest dose tested in the initial study, while the other half will receive placebo.

  1. Hammon HK, Penny WF, Traverse JH, et al. Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients with Heart Failure: A Randomized Clinical Trial. JAMA Cardiol. 2016;1(2):163-171. doi:10.1001/jamacardio.2016.0

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