Sensitivity Analysis of Vagus Nerve Stimulation Parameters on Acute Cardiac Autonomic Responses: Chronotropic, Inotropic and Dromotropic Effects.
Although the therapeutic effects of Vagus Nerve Stimulation (VNS) have been recognized in pre-clinical and pilot clinical studies, the effect of different stimulation configurations on the cardiovascular response is still an open question, especially in the case of VNS delivered synchronously with cardiac activity. In this paper, we propose a formal mathematical methodology to analyze the acute cardiac response to different VNS configurations, jointly considering the chronotropic, dromotropic and inotropic cardiac effects. A latin hypercube sampling method was chosen to design a uniform experimental plan, composed of 75 different VNS configurations, with different values for the main parameters (current amplitude, number of delivered pulses, pulse width, interpulse period and the delay between the detected cardiac event and VNS onset). These VNS configurations were applied to 6 healthy, anesthetized sheep, while acquiring the associated cardiovascular response. Unobserved VNS configurations were estimated using a Gaussian process regression (GPR) model. In order to quantitatively analyze the effect of each parameter and their combinations on the cardiac response, the Sobol sensitivity method was applied to the obtained GPR model and inter-individual sensitivity markers were estimated using a bootstrap approach. Results highlight the dominant effect of pulse current, pulse width and number of pulses, which explain respectively 49.4%, 19.7% and 6.0% of the mean global cardiovascular variability provoked by VNS. More interestingly, results also quantify the effect of the interactions between VNS parameters. In particular, the interactions between current and pulse width provoke higher cardiac effects than the changes on the number of pulses alone (between 6 and 25% of the variability). Although the sensitivity of individual VNS parameters seems similar for chronotropic, dromotropic and inotropic responses, the interacting effects of VNS parameters provoke significantly different cardiac responses, showing the feasibility of a parameter-based functional selectivity. These results are of primary importance for the optimal, subject-specific definition of VNS parameters for a given therapy and may lead to new closed-loop methods allowing for the optimal adaptation of VNS therapy through time.
INSERM, U1099, Rennes, France.|Université de Rennes 1, LTSI, Rennes, France.
David
D
Ojeda
INSERM, U1099, Rennes, France.|Université de Rennes 1, LTSI, Rennes, France.
Virginie
V
Le Rolle
INSERM, U1099, Rennes, France.|Université de Rennes 1, LTSI, Rennes, France.
Hector M
HM
Romero-Ugalde
INSERM, U1099, Rennes, France.|Université de Rennes 1, LTSI, Rennes, France.
Clément
C
Gallet
Sorin CRM SAS (a LivaNova company), Clamart, France.
Jean-Luc
JL
Bonnet
Sorin CRM SAS (a LivaNova company), Clamart, France.
Christine
C
Henry
INSERM, UMR970 Paris Cardio-vascular Research Center, Paris, France.|Assistance Publique-Hôpitaux de Paris, Department of Cardiology, Hôpital Européen Georges Pompidou, Paris, France.|Paris Descartes University, PRES Paris Sorbonne, Paris, France.
Alain
A
Bel
INSERM, U1099, Rennes, France.|Université de Rennes 1, LTSI, Rennes, France.|CHU Rennes, Department of Cardiology, Rennes, France.|INSERM, CIC-IT 1414, Rennes, France.
Philippe
P
Mabo
INSERM, U1099, Rennes, France.|Université de Rennes 1, LTSI, Rennes, France.
Guy
G
Carrault
INSERM, U1099, Rennes, France.|Université de Rennes 1, LTSI, Rennes, France.
Alfredo I
AI
Hernández
Physiol Rep. 2016 Feb;4(2):null
26811057
J Neural Eng. 2016 Aug;13(4):041002
27351347
Circ Res. 1990 Oct;67(4):844-51
2208610
Heart Rhythm. 2009 Nov;6(11 Suppl):S76-81
19880077
Epilepsia. 1994 May-Jun;35(3):616-26
8026408
Circ Res. 1991 May;68(5):1471-81
2019002
Am J Physiol. 1984 Apr;246(4 Pt 2):H585-91
6720914
Am J Physiol Heart Circ Physiol. 2015 Nov;309(9):H1579-90
26371172
J Card Fail. 2016 Aug;22(8):639-42
26576716
J Neural Eng. 2009 Apr;6(2):026001
19213992
Circ Res. 1969 Mar;24(3):303-11
5766513
Am J Physiol Heart Circ Physiol. 2015 Nov 15;309(10 ):H1740-52
26371171
Am J Physiol. 1989 Feb;256(2 Pt 2):H428-33
2916675
Circ Res. 1970 Nov;27(5):635-46
5486240
Neuromodulation. 2006 Jul;9(3):214-20
22151709
Am J Physiol. 1982 Aug;243(2):H219-25
7114232
Biol Psychiatry. 2000 Feb 15;47(4):276-86
10686262
PLoS One. 2012;7(11):e42799
23189120
Nature. 2000 May 25;405(6785):458-62
10839541
Am J Physiol. 1979 Sep;237(3):H275-81
224714
Exp Neurol. 2011 Jan;227(1):62-8
20851118
Conf Proc IEEE Eng Med Biol Soc. 2014;2014:6262-5
25571428
Eur Heart J. 2015 Feb 14;36(7):425-33
25176942
IEEE Trans Biomed Eng. 2010 Mar;57(3):607-15
19171513
IEEE Trans Biomed Eng. 2016 Jul;63(7):1551-8
26571507
J Cardiovasc Transl Res. 2014 Apr;7(3):310-20
24500409
J Cardiovasc Electrophysiol. 1998 Mar;9(3):245-52
9554729
Conf Proc IEEE Eng Med Biol Soc. 2014;2014:526-9
25570012
Ann Thorac Surg. 1998 Mar;65(3):637-42
9527187
Cardiol J. 2010;17(6):638-44
21154273