Intramyocardial adenoviral vascular endothelial growth factor-D
adenovirus
angiogenesis
arrhythmias
gene therapy
refractory angina
vascular endothelial growth factor
Journal
The journal of gene medicine
ISSN: 1521-2254
Titre abrégé: J Gene Med
Pays: England
ID NLM: 9815764
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
13
06
2022
received:
01
05
2022
accepted:
19
06
2022
pubmed:
25
6
2022
medline:
19
8
2022
entrez:
24
6
2022
Statut:
ppublish
Résumé
The phase I KAT301 trial investigated the use of intramyocardial adenoviral vascular endothelial growth factor-D We analyzed non-invasive risk predictors of ventricular arrhythmias from 12-lead electrocardiography (ECG) as well as heart rate variability (HRV) and the incidence of arrhythmias from 24 h ambulatory ECG at baseline and 3 and 12 months after the GT. In addition, we analyzed the incidence of new-onset arrhythmias and pacemaker implantations during 8.2 years (range 6.3-10.4 years) of follow-up. We found no significant increase in arrhythmias, including supraventricular and ventricular ectopic beats, atrial fibrillation, non-sustained ventricular tachycardias, and life-threatening tachycardias, nor changes in the non-invasive risk predictors of ventricular arrhythmias in the AdVEGF-D treated patients. Instead, we found a significant improvement in the very low and high-frequency bands of HRV suggestive of improved cardiac autonomic regulation after GT. In conclusion, our results suggest that AdVEGF-D GT does not predispose to arrhythmias and might improve HRV metrics.
Sections du résumé
BACKGROUND
The phase I KAT301 trial investigated the use of intramyocardial adenoviral vascular endothelial growth factor-D
METHODS
We analyzed non-invasive risk predictors of ventricular arrhythmias from 12-lead electrocardiography (ECG) as well as heart rate variability (HRV) and the incidence of arrhythmias from 24 h ambulatory ECG at baseline and 3 and 12 months after the GT. In addition, we analyzed the incidence of new-onset arrhythmias and pacemaker implantations during 8.2 years (range 6.3-10.4 years) of follow-up.
RESULTS
We found no significant increase in arrhythmias, including supraventricular and ventricular ectopic beats, atrial fibrillation, non-sustained ventricular tachycardias, and life-threatening tachycardias, nor changes in the non-invasive risk predictors of ventricular arrhythmias in the AdVEGF-D treated patients. Instead, we found a significant improvement in the very low and high-frequency bands of HRV suggestive of improved cardiac autonomic regulation after GT.
CONCLUSIONS
In conclusion, our results suggest that AdVEGF-D GT does not predispose to arrhythmias and might improve HRV metrics.
Substances chimiques
Vascular Endothelial Growth Factor D
0
Banques de données
ClinicalTrials.gov
['NCT01002430']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3437Subventions
Organisme : Kuopio University Hospital Heart Center
Informations de copyright
© 2022 John Wiley & Sons Ltd.
Références
Mannheimer C, Camici P, Chester MR, et al. The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J. 2002;23(5):355-370. doi:10.1053/euhj.2001.2706
Henry TD, Satran D, Jolicoeur EM. Treatment of refractory angina in patients not suitable for revascularization [published correction appears in Nat Rev Cardiol. 2014 Feb;11(2):i]. Nat Rev Cardiol. 2014;11(2):78-95. doi:10.1038/nrcardio.2013.200
Davies A, Fox K, Galassi AR, Banai S, Ylä-Herttuala S, Lüscher TF. Management of refractory angina: an update. Eur Heart J. 2021;42(3):269-283. doi:10.1093/eurheartj/ehaa820
Ylä-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J. Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol. 2007;49(10):1015-1026. doi:10.1016/j.jacc.2006.09.053
Stacker SA, Stenvers K, Caesar C, et al. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J Biol Chem. 1999;274(45):32127-32136. doi:10.1074/jbc.274.45.32127
Rissanen TT, Markkanen JE, Gruchala M, et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res. 2003;92(10):1098-1106. doi:10.1161/01.RES.0000073584.46059.E3
Hartikainen J, Hassinen I, Hedman A, et al. Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up [published correction appears in Eur Heart J. 2018 May 7;39(18):1652]. Eur Heart J. 2017;38(33):2547-2555. doi:10.1093/eurheartj/ehx352
Leikas AJ, Hassinen I, Hedman A, Kivelä A, Ylä-Herttuala S, Hartikainen JEK. Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study. Gene Ther. 2022;29(5):289-293. doi:10.1038/s41434-021-00295-1
Lähteenvuo J, Hätinen OP, Kuivanen A, et al. Susceptibility to Cardiac Arrhythmias and Sympathetic Nerve Growth in VEGF-B Overexpressing Myocardium. Mol Ther. 2020;28(7):1731-1740. doi:10.1016/j.ymthe.2020.03.011
Olofsson B, Pajusola K, von Euler G, Chilov D, Alitalo K, Eriksson U. Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J Biol Chem. 1996;271(32):19310-19317. doi:10.1074/jbc.271.32.19310
Menasché P. Cardiac cell therapy: lessons from clinical trials. J Mol Cell Cardiol. 2011;50(2):258-265. doi:10.1016/j.yjmcc.2010.06.010
Fukushima S, Varela-Carver A, Coppen SR, et al. Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular arrhythmias in a rat chronic ischemic heart failure model. Circulation. 2007;115(17):2254-2261. doi:10.1161/CIRCULATIONAHA.106.662577
Hassinen I, Kivelä A, Hedman A, et al. Intramyocardial Gene Therapy Directed to Hibernating Heart Muscle Using a Combination of Electromechanical Mapping and Positron Emission Tomography. Hum Gene Ther. 2016;27(10):830-834. doi:10.1089/hum.2016.131
Pelli A, Kenttä TV, Junttila MJ, et al. Electrocardiogram as a predictor of survival without appropriate shocks in primary prophylactic ICD patients: A retrospective multi-center study. Int J Cardiol. 2020;309:78-83. doi:10.1016/j.ijcard.2020.03.024
Perkiömäki JS, Koistinen MJ, Yli-Mäyry S, Huikuri HV. Dispersion of QT interval in patients with and without susceptibility to ventricular tachyarrhythmias after previous myocardial infarction. J Am Coll Cardiol. 1995;26(1):174-179. doi:10.1016/0735-1097(95)00122-g
Bigger JT Jr, Fleiss JL, Kleiger R, Miller JP, Rolnitzky LM. The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation. 1984;69(2):250-258. doi:10.1161/01.cir.69.2.250
La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998;351(9101):478-484. doi:10.1016/s0140-6736(97)11144-8
Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J. 1996;17(3):354-381.
Hedman M, Muona K, Hedman A, et al. Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer. Gene Ther. 2009;16(5):629-634. doi:10.1038/gt.2009.4
Muona K, Mäkinen K, Hedman M, Manninen H, Ylä-Herttuala S. 10-year safety follow-up in patients with local VEGF gene transfer to ischemic lower limb. Gene Ther. 2012;19(4):392-395. doi:10.1038/gt.2011.109
Giacca M, Recchia FA. VEGF-B Gene Therapy for the Heart: Proceed with Caution. Mol Ther. 2020;28(7):1566-1568. doi:10.1016/j.ymthe.2020.06.014
Stewart DJ, Hilton JD, Arnold JM, et al. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment. Gene Ther. 2006;13(21):1503-1511. doi:10.1038/sj.gt.3302802
Kastrup J, Jørgensen E, Fuchs S, et al. A randomised, double-blind, placebo-controlled, multicentre study of the safety and efficacy of BIOBYPASS (AdGVVEGF121.10NH) gene therapy in patients with refractory advanced coronary artery disease: the NOVA trial. EuroIntervention. 2011;6(7):813-818. doi:10.4244/EIJV6I7A140
Lyon AR, Bannister ML, Collins T, et al. SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure. Circ Arrhythm Electrophysiol. 2011;4(3):362-372. doi:10.1161/CIRCEP.110.961615
Chung ES, Miller L, Patel AN, et al. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized Phase II trial. Eur Heart J. 2015;36(33):2228-2238. doi:10.1093/eurheartj/ehv254
Oesterle SN, Sanborn TA, Ali N, et al. Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial. Potential Class Improvement From Intramyocardial Channels. Lancet. 2000;356(9243):1705-1710. doi:10.1016/s0140-6736(00)03203-7
Leon MB, Kornowski R, Downey WE, et al. A blinded, randomized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease. J Am Coll Cardiol. 2005;46(10):1812-1819. doi:10.1016/j.jacc.2005.06.079
Iuliano S, Fisher SG, Karasik PE, Fletcher RD, Singh SN. Department of Veterans Affairs Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. QRS duration and mortality in patients with congestive heart failure. Am Heart J. 2002;143(6):1085-1091. doi:10.1067/mhj.2002.122516
Chugh SS, Reinier K, Singh T, et al. Determinants of prolonged QT interval and their contribution to sudden death risk in coronary artery disease: the Oregon Sudden Unexpected Death Study. Circulation. 2009;119(5):663-670. doi:10.1161/CIRCULATIONAHA.108.797035
Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Trohman RG. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J. 2007;153(6):891-899. doi:10.1016/j.ahj.2007.01.040
Perkiömäki JS, Huikuri HV, Koistinen JM, Mäkikallio T, Castellanos A, Myerburg RJ. Heart rate variability and dispersion of QT interval in patients with vulnerability to ventricular tachycardia and ventricular fibrillation after previous myocardial infarction. J Am Coll Cardiol. 1997;30(5):1331-1338. doi:10.1016/s0735-1097(97)00301-x
Hartikainen JE, Malik M, Staunton A, Poloniecki J, Camm AJ. Distinction between arrhythmic and nonarrhythmic death after acute myocardial infarction based on heart rate variability, signal-averaged electrocardiogram, ventricular arrhythmias and left ventricular ejection fraction. J Am Coll Cardiol. 1996;28(2):296-304. doi:10.1016/0735-1097(96)00169-6
Wennerblom B, Lurje L, Solem J, et al. Reduced heart rate variability in ischemic heart disease is only partially caused by ischemia. An HRV study before and after PTCA. Cardiology. 2000;94(3):146-151. doi:10.1159/000047309
Bigger JT Jr, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation. 1992;85(1):164-171. doi:10.1161/01.cir.85.1.164
Shaffer F, McCraty R, Zerr CL. A healthy heart is not a metronome: an integrative review of the heart's anatomy and heart rate variability. Front Psychol. 2014;5:1040. doi:10.3389/fpsyg.2014.01040