The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial

Nigel E Drury, Neil J Howell, Melanie J Calvert, Ralf J M Weber, Eshan L Senanayake, Michael E Lewis, Jonathan A J Hyde, David H Green, Jorge G Mascaro, Ian C Wilson, Timothy R Graham, Stephen J Rooney, Mark R Viant, Nick Freemantle, Michael P Frenneaux, Domenico Pagano, investigators, Lynne K Williams, Aaron M Ranasinghe, David Hauton, Robert Cramb, Uday Dandekar, Andrew S Cohen, Robert Kong, Nina Cooter, Emma Gardner, Ailie MacKenzie, Nigel E Drury, Neil J Howell, Melanie J Calvert, Ralf J M Weber, Eshan L Senanayake, Michael E Lewis, Jonathan A J Hyde, David H Green, Jorge G Mascaro, Ian C Wilson, Timothy R Graham, Stephen J Rooney, Mark R Viant, Nick Freemantle, Michael P Frenneaux, Domenico Pagano, investigators, Lynne K Williams, Aaron M Ranasinghe, David Hauton, Robert Cramb, Uday Dandekar, Andrew S Cohen, Robert Kong, Nina Cooter, Emma Gardner, Ailie MacKenzie

Abstract

Objectives: Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome.

Methods: In a prospective, randomized, double-blind, placebo-controlled trial, patients at two centres were randomized to receive either oral perhexiline or placebo for at least 5 days prior to surgery. The primary outcome was a low cardiac output episode in the first 6 h. All pre-specified analyses were conducted according to the intention-to-treat principle with a statistical power of 90% to detect a relative risk of 0.5 and a conventional one-sided α-value of 0.025. A subset of pre-ischaemic left ventricular biopsies was analysed using mass spectrometry-based metabolomics.

Results: Over a 3-year period, 286 patients were randomized, received the intervention and were included in the analysis. The incidence rate of a low cardiac output episode in the perhexiline arm was 36.7% (51/139) vs 34.7% (51/147) in the control arm [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.56-1.50, P = 0.74]. Perhexiline was associated with a reduction in the cardiac index at 6 h [difference in means 0.19, 95% CI 0.07-0.31, P = 0.001] and an increase in inotropic support in the first 12 h (OR 0.55, 95% CI 0.34-0.89, P = 0.015). There were no significant differences in myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction or length of stay. No difference in the preischaemic left ventricular metabolism was identified between groups on metabolomics analysis.

Conclusions: Preoperative perhexiline does not improve myocardial protection in patients undergoing coronary surgery and in fact reduced perioperative cardiac output, increasing the need for inotropic support. Perhexiline has no significant effect on the mass spectrometry-visible polar myocardial metabolome in vivo in humans, supporting the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition and may explain the lack of clinical benefit observed following surgery.

Clinicaltrialsgov id: NCT00845364.

Keywords: Cardiac output; Metabolism; Metabolomics; Myocardial reperfusion injury; Myocardial stunning.

© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.

Figures

Figure 1:
Figure 1:
Participant flow diagram.
Figure 2:
Figure 2:
Mean cardiac index (l/min/m2) between treatment groups. Error bars represent 95% confidence intervals (CI) for the mean (P = 0.018 at 6 h).
Figure 3:
Figure 3:
Area under the concentration–time curve for serum troponin-T (ng h/ml) (P = 0.12).
Figure 4:
Figure 4:
Principal components analysis scores plot from negative ion Fourier transform ion cyclotron resonance mass spectra of left ventricular extracts: 21 control samples (blue) and 22 perhexiline samples (red), shows no metabolic response to perhexiline along the PC1 and PC2 axes. All eight quality control samples (X) are in a narrow cluster, confirming the consistency of mass spectrometry instrument performance over time.

References

    1. Bridgewater B, Keogh BE, Kinsman R, Walton P. Henley-on-Thames: Dendrite Clinical Systems, Ltd; 2009. Sixth National Adult Cardiac Surgery Database Report 2008. Demonstrating Quality.
    1. Doenst T, Borger MA, Weisel RD, Yau TM, Maganti M, Rao V. Relation between aortic cross-clamp time and mortality—not as straightforward as expected. Eur J Cardiothorac Surg. 2008;33:660–5.
    1. Fremes SE, Tamariz MG, Abramov D, Christakis GT, Sever JY, Sykora K, et al. Late results of the Warm Heart Trial: the influence of nonfatal cardiac events on late survival. Circulation. 2000;102:III339–345.
    1. Doenst T, Bugger H, Schwarzer M, Faerber G, Borger MA, Mohr FW. Three good reasons for heart surgeons to understand cardiac metabolism. Eur J Cardiothorac Surg. 2008;33:862–71.
    1. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207–58.
    1. Quinn DW, Pagano D, Bonser RS, Rooney SJ, Graham TR, Wilson IC, et al. Improved myocardial protection during coronary artery surgery with glucose-insulin-potassium: a randomized controlled trial. J Thorac Cardiovasc Surg. 2006;131:34–42.
    1. Howell NJ, Ashrafian H, Drury NE, Ranasinghe AM, Contractor H, Isackson H, et al. Glucose-insulin-potassium reduces the incidence of low cardiac output episodes after aortic valve replacement for aortic stenosis in patients with left ventricular hypertrophy: results from the Hypertrophy, Insulin, Glucose, and Electrolytes (HINGE) Trial. Circulation. 2011;123:170–7.
    1. Cole PL, Beamer AD, McGowan N, Cantillon CO, Benfell K, Kelly RA, et al. Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation. 1990;81:1260–70.
    1. Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation. 2005;112:3280–8.
    1. Abozguia K, Elliott P, McKenna W, Phan TT, Nallur-Shivu G, Ahmed I, et al. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation. 2010;122:1562–9.
    1. Horowitz JD, Sia ST, Macdonald PS, Goble AJ, Louis WJ. Perhexiline maleate treatment for severe angina pectoris--correlations with pharmacokinetics. Int J Cardiol. 1986;13:219–29.
    1. Kennedy JA, Unger SA, Horowitz JD. Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. Biochem Pharmacol. 1996;52:273–80.
    1. Griffin JL, Atherton H, Shockcor J, Atzori L. Metabolomics as a tool for cardiac research. Nat Rev Cardiol. 2011;8:630–43.
    1. Wu H, Southam AD, Hines A, Viant MR. High-throughput tissue extraction protocol for NMR- and MS-based metabolomics. Anal Biochem. 2008;372:204–12.
    1. Weber RJM, Southam AD, Sommer U, Viant MR. Characterization of isotopic abundance measurements in high resolution FT-ICR and Orbitrap mass spectra for improved confidence of metabolite identification. Anal Chem. 2011;83:3737–43.
    1. Southam AD, Payne TG, Cooper HJ, Arvanitis TN, Viant MR. Dynamic range and mass accuracy of wide-scan direct infusion nanoelectrospray Fourier transform ion cyclotron resonance mass spectrometry-based metabolomics increased by the spectral stitching method. Anal Chem. 2007;79:4595–602.
    1. Payne TG, Southam AD, Arvanitis TN, Viant MR. A signal filtering method for improved quantification and noise discrimination in Fourier transform ion cyclotron resonance mass spectrometry-based metabolomics data. J Am Soc Mass Spectrom. 2009;20:1087–95.
    1. Hrydziuszko O, Viant MR. Missing values in mass spectrometry based metabolomics: an undervalued step in the data processing pipeline. Metabolomics. 2012;(Suppl 8):161–74.
    1. Weber RJM, Viant MR. MI-Pack: increased confidence of metabolite identification in mass spectra by integrating accurate masses and metabolic pathways. Chemom Intell Lab Syst. 2010;104:75–82.
    1. Benjamini Y, Hochberg Y. Controlling the false discovery rate—a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57:289–300.
    1. Parsons HM, Ekman DR, Collette TW, Viant MR. Spectral relative standard deviation: a practical benchmark in metabolomics. Analyst. 2009;134:478–85.
    1. Fan Y, Zhang AM, Xiao YB, Weng YG, Hetzer R. Glucose-insulin-potassium therapy in adult patients undergoing cardiac surgery: a meta-analysis. Eur J Cardiothorac Surg. 2011;40:192–9.
    1. Yin X, Dwyer J, Langley SR, Mayr U, Xing Q, Drozdov I, et al. Effects of perhexiline-induced fuel switch on the cardiac proteome and metabolome. J Mol Cell Cardiol. 2013;55:27–30.
    1. Unger SA, Kennedy JA, McFadden-Lewis K, Minerds K, Murphy GA, Horowitz JD. Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium. J Cardiovasc Pharmacol. 2005;46:849–55.
    1. Ngo DT, Drury NE, Frenneaux M, Pagano D, Horowitz JD. How does perhexiline modulate myocardial energetics and ameliorate redox stress? Circulation. 2011;124:14461. Abstract.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever