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01-05-2021 | Neurotomy | Original Paper

Myocardial salvage is increased after sympathetic renal denervation in a pig model of acute infarction

Authors: Luigi Emilio Pastormerlo, Silvia Burchielli, Marco Ciardetti, Giovanni Donato Aquaro, Chrysantos Grigoratos, Vincenzo Castiglione, Angela Pucci, Maria Franzini, Assuero Giorgetti, Paolo Marzullo, Eleonora Benelli, Silvia Masotti, Veronica Musetti, Fabio Bernini, Sergio Berti, Claudio Passino, Michele Emdin

Published in: Clinical Research in Cardiology | Issue 5/2021

Abstract

Rationale

Despite advances in treatment of acute myocardial infarction (AMI), many patients suffer significant myocardial damage with cardiac dysfunction. Sympathetic renal denervation (RD) may reduce adrenergic activation following AMI.

Objective

To investigate the potential role of RD limiting myocardial damage and remodeling when performed immediately after AMI.

Methods and results

Sixteen farm pigs underwent 90 min left anterior descending artery balloon occlusion. Eight pigs underwent RD immediately after reperfusion. LV function, extent of myocardium at risk, and myocardial necrosis were quantified by cardiac magnetic resonance 5 and 30 days after AMI. ¹²³I-MIBG scintigraphy was performed 31 days after AMI to image myocardial sympathetic innervation. Heart norepinephrine was quantified (from necrotic, border and remote zone). RD and control did not differ in myocardium at risk extent (59 ± 9 vs 55 ± 11% of LV mass) at 5 days. At 30 days CMR, RD pigs had smaller necrotic areas than control as assessed by gadolinium delay enhancement (18 ± 7 vs 30 ± 12% of LV mass, p = 0.021) resulting in improved myocardial salvage index (60 ± 11 vs 44 ± 27%, p < 0.001). RD pigs had higher cardiac output (3.7 ± 0.8 vs 2.66 ± 0.7 L/min, p < 0.001) and lower LV end diastolic volume (98 ± 16 vs 113 ± 31 ml, p = 0.041). ¹²³I-MIBG defect extension was smaller in RD than control (60 ± 28 vs 78 ± 17%, p < 0.05) with significant reduction in the difference between innervation and perfusion defects (25 ± 12 vs 36 ± 30%, p = 0.013). NE content from necrotic area (238; IQR 464 vs 2546; IQR 1727 ng/g in RD and control, respectively, p < 0.001) and from border zone (295; IQR 264 vs 837; IQR 207 in RD and control, respectively, p = 0.031) was significantly lower in RD than control.

Conclusions

RD results in increased myocardial salvage and better cardiac function, when performed immediately after AMI. Reduction of sympathetic activation with preservation of cardiac sympathetic functionality warranted by RD may sustain these effects.

Graphic abstract

Available only for authorised users

Maeng M, Busk M, Mortensen LS, Kristensen SD, Nielsen TT, Andersen HR, DANAMI-2 Investigators (2010) Primary angioplasty versus fibrinolysis in acute myocardial infarction: long-term follow-up in the Danish acute myocardial infarction 2 trial. Circulation 121:1484–1491. https://doi.org/10.1016/j.amjcard.2009.03.014CrossRefPubMed

Rezkalla SH, Kloner RA (2002) No-reflow phenomenon. Circulation 105:656–662. https://doi.org/10.1161/hc0502.102867CrossRefPubMed

Feistritzer HJ, Meyer-Saraei R, Lober C, Böhm M, Scheller B, Lauer B, Geisler T, Gawaz M, Bruch L, Klein N, Zeymer U, Eitel I, Jobs A, Freund A, Desch S, de Waha-Thiele S, Thiele H (2020) Long-term outcome after thrombus aspiration in non-ST-elevation myocardial infarction: results from the TATORT-NSTEMI trial : thrombus aspiration in acute myocardial infarction. Clin Res Cardiol. https://doi.org/10.1007/s00392-020-01613-0CrossRefPubMedPubMedCentral

Backhaus SJ, Kowallick JT, Stiermaier T, Lange T, Koschalka A, Navarra JL, Lotz J, Kutty S, Bigalke B, Gutberlet M, Feistritzer HJ, Hasenfuß G, Thiele H, Schuster A, Eitel I (2020) Culprit vessel-related myocardial mechanics and prognostic implications following acute myocardial infarction. Clin Res Cardiol 109(3):339–349. https://doi.org/10.1007/s00392-019-01514-xCrossRefPubMed

Hartikainen J, Fyhrquist F, Tahvanainen K, Länsimies E, Pyörälä K (1995) Baroreflex sensitivity and neurohormonal activation in patients with acute myocardial infarction. Br Heart J 74:21–26. https://doi.org/10.1136/hrt.74.1.21CrossRefPubMedPubMedCentral

Jardine DL, Charles CJ, Ashton RK, Bennett SI, Whitehead M, Frampton CM, Nicholls MG (2005) Increased cardiac sympathetic nerve activity following acute myocardial infarction in a sheep model. J Physiol 565:325–333. https://doi.org/10.1113/jphysiol.2004.082198CrossRefPubMedPubMedCentral

Sutton MG, Sharpe N (2000) Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 101:2981–2998. https://doi.org/10.1161/01.CIR.101.25.2981CrossRefPubMed

Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI (1986) Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 73:615–621. https://doi.org/10.1161/01.CIR.73.4.615CrossRefPubMed

DiBona GF, Sawin LL (1991) Role of renal nerves in sodium retention of cirrhosis and congestive heart failure. Am J Physiol 260:R298–305. https://doi.org/10.1152/ajpregu.1991.260.2.R298CrossRefPubMed

10.

Allen AM, Moeller I, Jenkins TA, Zhuo J, Aldred GP, Chai SY, Mendelsohn FA (1998) Angiotensin receptors in the nervous system. Brain Res Bull 47:17–28. https://doi.org/10.1016/S0361-9230(98)00039-2CrossRefPubMed

11.

Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimský P, ESC Scientific Document Group (2018) 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 39:119–177. https://doi.org/10.1093/eurheartj/ehx393CrossRefPubMed

12.

Stienen S, Rossignol P, Barros A, Girerd N, Pitt B, Zannad F, Ferreira JP (2020) Determinants of anti-fibrotic response to mineralocorticoid receptor antagonist therapy: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) and Early Eplerenone Treatment in Patients with Acute ST-elevation Myocardial Infarction without Heart Failure (REMINDER) trials. Clin Res Cardiol 109(2):194–204. https://doi.org/10.1007/s00392-019-01500-3CrossRefPubMed

13.

Frankenstein L, Zugck C, Schellberg D, Nelles M, Froehlich H, Katus H, Remppis A (2009) Prevalence and prognostic significance of adrenergic escape during chronic beta-blocker therapy in chronic heart failure. Eur J Heart Fail 11:178–184. https://doi.org/10.1093/eurjhf/hfn028CrossRefPubMedPubMedCentral

14.

Masson S, Solomon S, Angelici L, Latini R, Anand IS, Prescott M, Maggioni AP, Tognoni G, Cohn JN, Val-Heft Investigators (2010) Elevated plasma renin activity predicts adverse outcome in chronic heart failure, independently of pharmacologic therapy: data from the Valsartan Heart Failure Trial (Val-HeFT). J Card Fail 16:964–970. https://doi.org/10.1016/j.cardfail.2010.06.417CrossRefPubMed

15.

Ciardetti M, Coceani M, Pastormerlo LE, Fommei E, Ghione S, Passino C, Emdin M, Palmieri C, Berti S (2015) Renal denervation in resistant arterial hypertension: effects on neurohormonal activation and cardiac natriuretic peptides. Int J Cardiol 184:574–575. https://doi.org/10.1016/j.ijcard.2015.03.023CrossRefPubMed

16.

Polhemus DJ, Gao J, Scarborough AL, Trivedi R, McDonough KH, Goodchild TT, Smart F, Kapusta DR, Lefer DJ (2016) Radiofrequency renal denervation protects the ischemic heart via inhibition of GRK2 and increased nitric oxide signaling. Circ Res 119:470–480. https://doi.org/10.1161/CIRCRESAHA.115.308278CrossRefPubMedPubMedCentral

17.

Polhemus DJ, Trivedi RK, Gao J, Li Z, Scarborough AL, Goodchild TT, Varner KJ, Xia H, Smart FW, Kapusta DR, Lefer DJ (2017) Renal sympathetic denervation protects the failing heart via inhibition of neprilysin activity in the kidney. J Am Coll Cardiol 70:2139–2153. https://doi.org/10.1016/j.jacc.2017.08.056CrossRefPubMed

18.

Sharp TE, Polhemus DJ, Li Z, Spaletra P, Jenkins JS, Reilly JP, White CJ, Kapusta DR, Lefer DJ, Goodchild TT (2018) Renal denervation prevents heart failure progression via inhibition of the renin-angiotensin system. J Am Coll Cardiol 72:2609–2621. https://doi.org/10.1016/j.jacc.2018.08.2186CrossRefPubMed

19.

Mahfoud F, Moon LB, Pipenhagen CA, Jensen JA, Pathak A, Papademetriou V, Ewen S, Linz D, Böhm M (2016) Catheter-based radio-frequency renal nerve denervation lowers blood pressure in obese hypertensive swine model. J Hypertens 34:1854–1862. https://doi.org/10.1097/hjh.0000000000001021CrossRefPubMed

20.

Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 22:680–685. https://doi.org/10.1038/227680a0CrossRef

21.

Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL, SYMPLICITY HTN-3 Investigators (2014) A controlled trial of renal denervation for resistant hypertension. N Engl J Med 370:1393–1401. https://doi.org/10.1056/NEJMoa1402670CrossRefPubMed

22.

Böhm M, Townsend RR, Kario K, Kandzari D, Mahfoud F, Weber MA, Schmieder RE, Tsioufis K, Hickey GL, Fahy M, DeBruin V, Brar S, Pocock S (2020) Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design. Clin Res Cardiol 109(3):289–302. https://doi.org/10.1007/s00392-020-01595-zCrossRefPubMedPubMedCentral

23.

Kandzari DE, Böhm M, Mahfoud F, Townsend RR, Weber MA, Pocock S, Tsioufis K, Tousoulis D, Choi JW, East C, Brar S, Cohen SA, Fahy M, Pilcher G, Kario K, SPYRAL HTN-ON MED Trial Investigators (2018) Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet 391:2346–2355. https://doi.org/10.1016/S0140-6736(18)30951-6CrossRefPubMed

24.

Azizi M, Schmieder RE, Mahfoud F, Weber MA, Daemen J, Davies J, Basile J, Kirtane AJ, Wang Y, Lobo MD, Saxena M, Feyz L, Rader F, Lurz P, Sayer J, Sapoval M, Levy T, Sanghvi K, Abraham J, Sharp ASP, Fisher NDL, Bloch MJ, Reeve-Stoffer H, Coleman L, Mullin C, Mauri L, RADIANCE-HTN Investigators (2018) Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet 391:2335–2345. https://doi.org/10.1016/S0140-6736(18)31082-1CrossRefPubMed

25.

Mahfoud F, Schmieder RE, Azizi M, Pathak A, Sievert H, Tsioufis C, Zeller T, Bertog S, Blankestijn PJ, Böhm M, Burnier M, Chatellier G, Durand Zaleski I, Ewen S, Grassi G, Joner M, Kjeldsen SE, Lobo MD, Lotan C, Lüscher TF, Parati G, Rossignol P, Ruilope L, Sharif F, van Leeuwen E, Volpe M, Windecker S, Witkowski A, Wijns W (2017) Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future. Eur Heart J 38:3272–3281. https://doi.org/10.1093/eurheartj/ehx215CrossRefPubMedPubMedCentral

26.

Ukena C, Seidel T, Rizas K, Scarsi D, Millenaar D, Ewen S, Bauer A, Mahfoud F, Böhm M (2019) Effects of renal denervation on 24-h heart rate and heart rate variability in resistant hypertension. Clin Res Cardiol. https://doi.org/10.1007/s00392-019-01543-6CrossRefPubMed

27.

Linz D, Wirth K, Ukena C, Mahfoud F, Pöss J, Linz B, Böhm M, Neuberger HR (2013) Renal denervation suppresses ventricular arrhythmias during acute ventricular ischemia in pigs. Heart Rhythm 10:1525–1530. https://doi.org/10.1016/j.hrthm.2013.07.015CrossRefPubMed

28.

Huang B, Yu L, He B, Lu Z, Wang S, He W, Yang K, Liao K, Zhang L, Jiang H (2014) Renal sympathetic denervation modulates ventricular electrophysiology and has a protective effect on ischaemia-induced ventricular arrhythmia. Exp Physiol 99:1467–1477. https://doi.org/10.1113/expphysiol.2014.082057CrossRefPubMed

29.

Jackson N, Gizurarson S, Azam MA, King B, Ramadeen A, Zamiri N, Porta-Sánchez A, Al-Hesayen A, Graham J, Kusha M, Massé S, Lai PF, Parker J, John R, Kiehl TR, Nair GK, Dorian P, Nanthakumar K (2017) Effects of renal artery denervation on ventricular arrhythmias in a Postinfarct model. Circ Cardiovasc Interv 10:e004172. https://doi.org/10.1161/CIRCINTERVENTIONSCrossRefPubMed

30.

Dall’Armellina E, Karamitsos TD, Neubauer S, Choudhury RP (2017) CMR for characterization of the myocardium in acute coronary syndromes. Nat Rev Cardiol 7:624–636. https://doi.org/10.1038/nrcardio.2010.140CrossRef

31.

Masci PG, Ganame J, Strata E, Desmet W, Aquaro GD, Dymarkowski S, Valenti V, Janssens S, Lombardi M, Van de Werf F, L'Abbate A, Bogaert J (2010) Myocardial salvage by CMR correlates with LV remodeling and early ST-segment resolution in acute myocardial infarction. JACC Cardiovasc Imaging 3:45–51. https://doi.org/10.1016/j.jcmg.2009.06.016CrossRefPubMed

32.

Musiolik J, van Caster P, Skyschally A, Boengler K, Gres P, Schulz R, Heusch G (2010) Reduction of infarct size by gentle reperfusion without activation of reperfusion injury salvage kinases in pigs. Cardiovasc Res 85:110–117. https://doi.org/10.1093/cvr/cvp271CrossRefPubMed

33.

Arimura T, Saku K, Kakino T, Nishikawa T, Tohyama T, Sakamoto T, Sakamoto K, Kishi T, Ide T, Sunagawa K (2017) Intravenous electrical vagal nerve stimulation prior to coronary reperfusion in a canine ischemia-reperfusion model markedly reduces infarct size and prevents subsequent heart failure. Int J Cardiol 227:704–710. https://doi.org/10.1016/j.ijcard.2016.10.074CrossRefPubMed

34.

Todd GL, Baroldi G, Pieper GM, Clayton FC, Eliot RS (1985) Experimental catecholamine induced myocardial necrosis. Morphology, quantification and regional distribution of acute contraction band lesions. J Mol Cell Cardiol 17:317–338. https://doi.org/10.1016/S0022-2828(85)80132-2CrossRefPubMed

35.

Uitterdijk A, Yetgin T, Lintel Hekkert M, Sneep S, Krabbendam-Peters I, van Beusekom HM, Fischer TM, Cornelussen RN, Manintveld OC, Merkus D, Duncker DJ (2015) Vagal nerve stimulation started just prior to reperfusion limits infarct size and no-reflow. Basic Res Cardiol 110:508. https://doi.org/10.1007/s00395-015-0508-3CrossRefPubMed

36.

Chen PS, Chen LS, Cao JM, Sharifi B, aragueuzian HS, Fishbein MC (2001) Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death. Cardiovasc Res 50:409–416. https://doi.org/10.1016/S0008-6363(00)00308-4CrossRefPubMed

37.

Schulte L, Peters D, Taylor J, Navarro J, Kandarian S (1994) Sarcoplasmic reticulum Ca²⁺ pump expression in denervated heart. Am J Physiol 267:C617–622. https://doi.org/10.1152/ajpcell.1994.267.2.C617CrossRefPubMed

Title: Myocardial salvage is increased after sympathetic renal denervation in a pig model of acute infarction
Authors: Luigi Emilio Pastormerlo
Silvia Burchielli
Marco Ciardetti
Giovanni Donato Aquaro
Chrysantos Grigoratos
Vincenzo Castiglione
Angela Pucci
Maria Franzini
Assuero Giorgetti
Paolo Marzullo
Eleonora Benelli
Silvia Masotti
Veronica Musetti
Fabio Bernini
Sergio Berti
Claudio Passino
Michele Emdin
Publication date: 01-05-2021
Publisher: Springer Berlin Heidelberg
Keywords: Neurotomy
Myocardial Infarction
Published in: Clinical Research in Cardiology / Issue 5/2021
Print ISSN: 1861-0684
Electronic ISSN: 1861-0692
DOI: https://doi.org/10.1007/s00392-020-01685-y

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Myocardial salvage is increased after sympathetic renal denervation in a pig model of acute infarction

Abstract

Rationale

Objective

Methods and results

Conclusions

Graphic abstract

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Abstract

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Objective

Methods and results

Conclusions

Graphic abstract

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