AC6 gene transfer is safe and increases LV function in HF patients
Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure
A Randomized Clinical Trial
Hammond KH, Penny WF, Traverse JH, et al.
JAMA Cardiol 2016; published online ahead of print
BackgroundHeart failure is increasing in prevalence and HF hospitalisation rates and mortality remained almost constant in the past decade, suggesting that new therapies are needed [1,2]. Gene transfer has barely been evaluated in clinical trials, although there is evidence suggesting that AC6 (adenylyl cyclase type 6) gene transfer might improve cardiac function [4-9]. AC6 is a 130-kD membrane protein that is dominant in heart muscle cells and that catalyses the conversion of cAMP, which, in turn, is important for heart function . Relevant AC6 data show that:
- increased cardiac AC6 content was beneficial for cardiomyocytes and the heart in preclinical studies 
- AC6 is reduced in failing hearts 
- the basal intracellular cAMP production is not altered by significant AC6 increases in preclinical models 
- AC6 influences heart function independently of cAMP, via calcium uptake regulation 
- Increased expression ofAC6 restored LV function in a genetic preclinical model of cardiomyopathy 
- expression of AC6 normalised prolonged action potential duration and reduced ventricular arrhythmias in cardiomyopathy 
High dose administration of Ad5.hAC6 resulted in:
- increased EF at 4 weeks: 29.7% vs. 36.3%; mean increase: +6.0 [+SE:1.7] EF units; n = 21; P< 0.004. This increase was dose-related (P < 0.04).
- not increased EF at 12 weeks: 29.7% vs. 34.2%; mean increase: +3.0 [2.4] EF units; n = 21; P=0.16
- at 4 weeks: 29.6% vs. 33.7%; mean increase: +4.1 [2.2] EF units; n= 14; P=0.08
- at 12 weeks: 29.6% vs. 31.6%: mean increase: +0.8 [1.2] EF units; n=13; P=0.42
Exercise duration showed no significant group differences in change from baseline between placebo and high dose, not at 4 weeks and not at 12 weeks.
HF symptoms and NYHA classification:
Administration of high dose Ad5.hAC6 led to a significant reduction in symptoms:
- 12 weeks after randomization: 28.8[2.4] vs. 20.5 [3.0]; n = 22; P = 0.0005)
- 4 week and 12 weeks: NYHA decrease by 1.0 unit (from 3.0 to 2.0); P < 0.11 at 4 weeks and P < 0.01 at 12weeks
- 9.5% (4 of 42) in the AC6 group
- 28.6%(4 of 14) in the placebo group
- AC6 gene transfer increased basal left ventricular peak −dP/dt. 4-week change from baseline: placebo: +93 mmHg/s; high dose Ad5.hAC6: −39 mmHg/s; placebo [n = 21]; P < 0.03
- AC6 did not increase arrhythmias
- No significant adverse events occurred during AC6 administration
ConclusionAC6 gene transfer by means of intracoronary delivery of Ad5.hAC6 in stable HF patients with reduced EF significantly increased the LV function, and was not associated with increased adverse events.
Find this article online at JAMA Cardiol
1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6-e245.
2. HallMJ, Levant S, DeFrances CJ. Hospitalization for Congestive Heart Failure: United States, 2000-2010. Hyattsville, MD: Centers for Disease Control and Prevention, National Center for Health Statistics; October 2012. National Center for Health Statistics, Data Brief, No. 108.
3. Sunahara RK, Dessauer CW, Gilman AG. Complexity and diversity of mammalian adenylyl cyclases. Annu Rev Pharmacol Toxicol. 1996;36:461-480.
4. Gao M, Ping P, Post S, et al. Increased expression of adenylylcyclase type VI proportionately increases β-adrenergic receptor–stimulated production of cAMP in neonatal rat cardiacmyocytes. Proc Natl Acad Sci U S A. 1998;95(3):1038-1043.
5. BristowMR, Ginsburg R,MinobeW, et al. Decreased catecholamine sensitivity and β-adrenergic–receptor density in failing human hearts. N Engl J Med. 1982;307(4):205-211.
6. Gao MH, Lai NC, Roth DM, et al. Adenylylcyclase increases responsiveness to catecholamine stimulation in transgenicmice. Circulation. 1999;99(12):1618-1622.
7. Tang T, Gao MH, Roth DM, et al. Adenylyl cyclase type VI corrects cardiac sarcoplasmic reticulum calcium uptake defects in cardiomyopathy. Am J Physiol Heart Circ Physiol.2004;287(5):H1906-H1912.
8. Roth DM, Bayat H, Drumm JD, et al. Adenylyl cyclase increases survival in cardiomyopathy. Circulation. 2002;105(16):1989-1994.
9. Timofeyev V, He Y, Tuteja D, et al. Cardiac-directed expression of adenylyl cyclase reverses electrical remodeling in cardiomyopathy. J Mol Cell Cardiol. 2006;41(1):170-181.