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Endothelial dysfunction in patients with angina and non-obstructed coronary arteries is associated with an increased risk of mayor cardiovascular events. Results of the Spanish ENDOCOR registry

Published:October 31, 2022DOI:https://doi.org/10.1016/j.ijcard.2022.10.169

      Highlights

      • Almost half of patients with INOCA have coronary endothelial dysfunction.
      • Exertional angina is a predictor of coronary endothelial dysfunction in INOCA.
      • Coronary endothelial dysfunction is a predictor of cardiovascular events in patients with INOCA.

      Abstract

      Background

      Coronary endothelial dysfunction and vasospasm are potential causes of ischemia in patients without obstructive coronary stenoses (INOCA).

      Objective

      To evaluate the prevalence of endothelial dysfunction and the clinical profile of patients with INOCA in Spain, as well as to identify the predictors and the prognostic impact of endothelial dysfunction in this scenario.

      Methods

      A total of 438 consecutive patients with INOCA in whom the acetylcholine test was performed were prospectively enrolled. Patients were followed up at 1 and 2 years.

      Results

      Mean age was 62 ± 11 years with 60% female. Clinical presentation comprised 52.6% angina at rest, 61.2% exertional angina, and 31.7% dyspnea. There were no major complications of the acetylcholine test. Endothelial dysfunction was observed in 198 (45%) of patients, with severe vasoconstriction (defined as over 70% constriction), being observed in 101 (23%).
      Multivariable regression analysis showed that endothelial dysfunction was predicted by the presence of exertional angina (OR 2.2; CI95%1.01–2.55; p = 0.02), prior coronary disease (OR 2.46; CI95% 1.57–3.89; p < 0.01), and coronary intramyocardial bridging (2.35; CI95% 1.02–5.60; p = 0.04).
      Patients with endothelial dysfunction presented with worsening angina compared to those without endothelial dysfunction (25.6% vs. 12.8%) and also presented with increased levels of minimal effort angina (40% vs. 26,7%, p = 0.03) more frequently during the follow up than those without endothelial dysfunction. Endothelial dysfunction was also an independent predictor of the occurrence of myocardial infarction or unstable angina at one year (OR 2.85, CI 95% 1.01–9.25; p = 0.03).

      Conclusions

      Endothelial dysfunction is present in almost half of patients with INOCA and is associated with worsening symptoms, as well as with a higher rate of adverse events.

      Graphical abstract

      Keywords

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      References

        • Wang Z.J.
        • Zhang L.L.
        • Elmariah S.
        • Han H.Y.
        • Zhou Y.J.
        Prevalence and prognosis of nonobstructive coronary artery disease in patients undergoing coronary angiography or coronary computed tomography angiography.
        Mayo Clin. Proc. 2017; 92: 329-346https://doi.org/10.1016/j.mayocp.2016.11.016
        • Gutierrez E.
        • Flammer A.J.
        • Lerman L.O.
        • Elizaga J.
        • Lerman A.
        • Fernandez-Aviles F.
        Endothelial dysfunction over the course of coronary artery disease.
        Eur. Heart J. 2013; 34: 3175-3181https://doi.org/10.1093/eurheartj/eht351
        • Schachinger V.
        • Britten M.B.
        • Zeiher A.M.
        Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease.
        Circulation. 2000; 101: 1899-1906
        • Gutiérrez E.
        • Gómez-Lara J.
        • Escaned J.
        • Cruz I.
        • Ojeda S.
        • Romaguera R.
        • Moreno R.
        Assessment of the endothelial function and spasm provocation test performed by intracoronary infusion of acetylcholine.
        in: Technical Report from the ACI-SEC, REC Interv. Cardiol. Engl. Ed. 2021: 6489https://doi.org/10.24875/RECICE.M21000215
        • Sara J.D.
        • Widmer R.J.
        • Matsuzawa Y.
        • Lennon R.J.
        • Lerman L.O.
        • Lerman A.
        Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease.
        JACC Cardiovasc. Interv. 2015; 8: 1445-1453https://doi.org/10.1016/j.jcin.2015.06.017
        • Hoshino M.
        • Yonetsu T.
        • Mizukami A.
        • Matsuda Y.
        • Yoshioka K.
        • Sudo Y.
        • Ninomiya R.
        • Soeda M.
        • Kuroda S.
        • Ono M.
        • Iwatsuka R.
        • Suzuki M.
        • Matsumura A.
        • Hashimoto Y.
        Moderate vasomotor response to acetylcholine provocation test as an indicator of long-term prognosis.
        Heart Vessel. 2016; https://doi.org/10.1007/s00380-016-0827-9
        • Ong P.
        • Athanasiadis A.
        • Borgulya G.
        • Vokshi I.
        • Bastiaenen R.
        • Kubik S.
        • Hill S.
        • Schaufele T.
        • Mahrholdt H.
        • Kaski J.C.
        • Sechtem U.
        Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries.
        Circulation. 2014; 129: 1723-1730https://doi.org/10.1161/CIRCULATIONAHA.113.004096
        • Knuuti J.
        • Wijns W.
        • Saraste A.
        • Capodanno D.
        • Barbato E.
        • Funck-Brentano C.
        • Prescott E.
        • Storey R.F.
        • Deaton C.
        • Cuisset T.
        • Agewall S.
        • Dickstein K.
        • Edvardsen T.
        • Escaned J.
        • Gersh B.J.
        • Svitil P.
        • Gilard M.
        • Hasdai D.
        • Hatala R.
        • Mahfoud F.
        • Masip J.
        • Muneretto C.
        • Valgimigli M.
        • Achenbach S.
        • Bax J.J.
        • ESC Scientific Document Group
        • Neumann F.-J.
        • Sechtem U.
        • Banning A.P.
        • Bonaros N.
        • Bueno H.
        • Bugiardini R.
        • Chieffo A.
        • Crea F.
        • Czerny M.
        • Delgado V.
        • Dendale P.
        • Flachskampf F.A.
        • Gohlke H.
        • Grove E.L.
        • James S.
        • Katritsis D.
        • Landmesser U.
        • Lettino M.
        • Matter C.M.
        • Nathoe H.
        • Niessner A.
        • Patrono C.
        • Petronio A.S.
        • Pettersen S.E.
        • Piccolo R.
        • Piepoli M.F.
        • Popescu B.A.
        • Räber L.
        • Richter D.J.
        • Roffi M.
        • Roithinger F.X.
        • Shlyakhto E.
        • Sibbing D.
        • Silber S.
        • Simpson I.A.
        • Sousa-Uva M.
        • Vardas P.
        • Witkowski A.
        • Zamorano J.L.
        • Achenbach S.
        • Agewall S.
        • Barbato E.
        • Bax J.J.
        • Capodanno D.
        • Cuisset T.
        • Deaton C.
        • Dickstein K.
        • Edvardsen T.
        • Escaned J.
        • Funck-Brentano C.
        • Gersh B.J.
        • Gilard M.
        • Hasdai D.
        • Hatala R.
        • Mahfoud F.
        • Masip J.
        • Muneretto C.
        • Prescott E.
        • Saraste A.
        • Storey R.F.
        • Svitil P.
        • Valgimigli M.
        • Windecker S.
        • Aboyans V.
        • Baigent C.
        • Collet J.-P.
        • Dean V.
        • Delgado V.
        • Fitzsimons D.
        • Gale C.P.
        • Grobbee D.
        • Halvorsen S.
        • Hindricks G.
        • Iung B.
        • Jüni P.
        • Katus H.A.
        • Landmesser U.
        • Leclercq C.
        • Lettino M.
        • Lewis B.S.
        • Merkely B.
        • Mueller C.
        • Petersen S.
        • Petronio A.S.
        • Richter D.J.
        • Roffi M.
        • Shlyakhto E.
        • Simpson I.A.
        • Sousa-Uva M.
        • Touyz R.M.
        • Benkhedda S.
        • Metzler B.
        • Sujayeva V.
        • Cosyns B.
        • Kusljugic Z.
        • Velchev V.
        • Panayi G.
        • Kala P.
        • Haahr-Pedersen S.A.
        • Kabil H.
        • Ainla T.
        • Kaukonen T.
        • Cayla G.
        • Pagava Z.
        • Woehrle J.
        • Kanakakis J.
        • Tóth K.
        • Gudnason T.
        • Peace A.
        • Aronson D.
        • Riccio C.
        • Elezi S.
        • Mirrakhimov E.
        • Hansone S.
        • Sarkis A.
        • Babarskiene R.
        • Beissel J.
        • Maempel A.J.C.
        • Revenco V.
        • de Grooth G.J.
        • Pejkov H.
        • Juliebø V.
        • Lipiec P.
        • Santos J.
        • Chioncel O.
        • Duplyakov D.
        • Bertelli L.
        • Dikic A.D.
        • Studenčan M.
        • Bunc M.
        • Alfonso F.
        • Bäck M.
        • Zellweger M.
        • Addad F.
        • Yildirir A.
        • Sirenko Y.
        • Clapp B.
        2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes.
        Eur. Heart J. 2019; https://doi.org/10.1093/eurheartj/ehz425
        • Kunadian V.
        • Chieffo A.
        • Camici P.G.
        • Berry C.
        • Escaned J.
        • Maas A.H.E.M.
        • Prescott E.
        • Karam N.
        • Appelman Y.
        • Fraccaro C.
        • Buchanan G. Louise
        • Manzo-Silberman S.
        • Al-Lamee R.
        • Regar E.
        • Lansky A.
        • Abbott J.D.
        • Badimon L.
        • Duncker D.J.
        • Mehran R.
        • Capodanno D.
        • Baumbach A.
        An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with european society of cardiology working group on coronary pathophysiology & microcirculation endorsed by coronary vasomotor disorders international study group.
        Eur. Heart J. 2020; https://doi.org/10.1093/eurheartj/ehaa503
        • Bourassa M.G.
        • Butnaru A.
        • Lespérance J.
        • Tardif J.-C.
        Symptomatic myocardial bridges: overview of ischemic mechanisms and current diagnostic and treatment strategies.
        J. Am. Coll. Cardiol. 2003; 41: 351-359https://doi.org/10.1016/S0735-1097(02)02768-7
        • Reriani M.
        • Sara J.D.
        • Flammer A.J.
        • Gulati R.
        • Li J.
        • Rihal C.
        • Lennon R.
        • Lerman L.O.
        • Lerman A.
        Coronary endothelial function testing provides superior discrimination compared with standard clinical risk scoring in prediction of cardiovascular events.
        Coron. Artery Dis. 2016; 27: 213-220https://doi.org/10.1097/MCA.0000000000000347
        • AlBadri A.
        • Bairey Merz C.N.
        • Johnson B.D.
        • Wei J.
        • Mehta P.K.
        • Cook-Wiens G.
        • Reis S.E.
        • Kelsey S.F.
        • Bittner V.
        • Sopko G.
        • Shaw L.J.
        • Pepine C.J.
        • Ahmed B.
        Impact of abnormal coronary reactivity on long-term clinical outcomes in women.
        J. Am. Coll. Cardiol. 2019; 73: 684-693https://doi.org/10.1016/j.jacc.2018.11.040
        • Sueda S.
        • Kohno H.
        • Fukuda H.
        • Ochi N.
        • Kawada H.
        • Hayashi Y.
        • Uraoka T.
        Induction of coronary artery spasm by two pharmacological agents: comparison between intracoronary injection of acetylcholine and ergonovine.
        Coron. Artery Dis. 2003; 14: 451-457
        • Montone R.A.
        • Rinaldi R.
        • Buono M.G.D.
        • Gurgoglione F.
        • Vecchia G.L.
        • Russo M.
        • Caffè A.
        • Burzotta F.
        • Leone A.M.
        • Romagnoli E.
        • Sanna T.
        • Pelargonio G.
        • Trani C.
        • Lanza G.A.
        • Niccoli G.
        • Crea F.
        Safety and prognostic relevance of acetylcholine testing in patients with stable myocardial ischaemia or myocardial infarction and non-obstructive coronary arteries.
        2022: 27
        • Feenstra Rutger G.T.
        • Seitz Andreas
        • Boerhout Coen K.M.
        • Bukkems Laura H.
        • Stegehuis Valérie E.
        • Teeuwisse Patty J.I.
        • de Winter Robbert J.
        • Sechtem Udo
        • Piek Jan J.
        • van de Hoef Tim P.
        • Ong Peter
        • Marcel A.M.
        Beijk, Principles and pitfalls in coronary vasomotor function testing.
        EuroIntervention. 2022; 17: 1271-1280
        • The ENCORE Investigators
        Effect of nifedipine and cerivastatin on coronary endothelial function in patients with coronary artery disease: the ENCORE I study (evaluation of nifedipine and cerivastatin on recovery of coronary endothelial function).
        Circulation. 2003; 107: 422-428https://doi.org/10.1161/01.CIR.0000046488.52939.BF
        • Luscher T.F.
        • Pieper M.
        • Tendera M.
        • Vrolix M.
        • Rutsch W.
        • van den Branden F.
        • Gil R.
        • Bischoff K.O.
        • Haude M.
        • Fischer D.
        • Meinertz T.
        • Munzel T.
        A randomized placebo-controlled study on the effect of nifedipine on coronary endothelial function and plaque formation in patients with coronary artery disease: the ENCORE II study.
        Eur. Heart J. 2009; 30: 1590-1597
        • Hasdai D.
        • Cannan C.R.
        • Mathew V.
        • Holmes Jr., D.R.
        • Lerman A.
        Evaluation of patients with minimally obstructive coronary artery disease and angina.
        Int. J. Cardiol. 1996; 53 (https://doi.org/0167527395025480 [pii]): 203-208
        • Díez-Delhoyo F.
        • Gutiérrez-Ibañes E.
        • Sanz-Ruiz R.
        • Vázquez-Álvarez M.E.
        • González Saldívar H.
        • Rivera Juárez A.
        • Sarnago F.
        • Martínez-Sellés M.
        • Bermejo J.
        • Soriano J.
        • Elízaga J.
        • Fernández-Avilés F.
        Prevalence of microvascular and endothelial dysfunction in the nonculprit territory in patients with acute myocardial infarction: the FISIOIAM study.
        Circ. Cardiovasc. Interv. 2019; 12https://doi.org/10.1161/CIRCINTERVENTIONS.118.007257
        • Beltrame J.F.
        • Crea F.
        • Kaski J.C.
        • Ogawa H.
        • Ong P.
        • Sechtem U.
        • Shimokawa H.
        • Bairey Merz C.N.
        On behalf of the coronary vasomotion disorders international study group (COVADIS), the who, what, why, when, how and where of vasospastic angina.
        Circ. J. 2016; 80: 289-298https://doi.org/10.1253/circj.CJ-15-1202
        • Beltrame J.F.
        • Tavella R.
        • Jones D.
        • Zeitz C.
        Management of ischaemia with non-obstructive coronary arteries (INOCA).
        BMJ. 2021; e060602https://doi.org/10.1136/bmj-2021-060602
        • Vita J.A.
        • Treasure C.B.
        • Nabel E.G.
        • McLenachan J.M.
        • Fish R.D.
        • Yeung A.C.
        • Vekshtein V.I.
        • Selwyn A.P.
        • Ganz P.
        Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.
        Circulation. 1990; 81: 491-497
        • Lavi S.
        • Bae J.H.
        • Rihal C.S.
        • Prasad A.
        • Barsness G.W.
        • Lennon R.J.
        • Holmes Jr., D.R.
        • Lerman A.
        Segmental coronary endothelial dysfunction in patients with minimal atherosclerosis is associated with necrotic core plaques.
        Heart. 2009; 95: 1525-1530https://doi.org/10.1136/hrt.2009.166017
        • Arai R.
        • Kano H.
        • Suzuki S.
        • Semba H.
        • Arita T.
        • Yagi N.
        • Otsuka T.
        • Matsuno S.
        • Matsuhama M.
        • Kato Y.
        • Uejima T.
        • Oikawa Y.
        • Okumura Y.
        • Yajima J.
        • Yamashita T.
        Myocardial bridging is an independent predictor of positive spasm provocation testing by intracoronary ergonovine injections: a retrospective observational study.
        Heart Vessel. 2020; 35: 474-486https://doi.org/10.1007/s00380-019-01518-7
        • Herrmann J.
        • Higano S.T.
        • Lenon R.J.
        • Rihal C.S.
        • Lerman A.
        Myocardial bridging is associated with alteration in coronary vasoreactivity.
        Eur. Heart J. 2004; 25: 2134-2142https://doi.org/10.1016/j.ehj.2004.08.015
        • Montone R.A.
        • Gurgoglione F.L.
        • Del Buono M.G.
        • Rinaldi R.
        • Meucci M.C.
        • Iannaccone G.
        • La Vecchia G.
        • Camilli M.
        • D’Amario D.
        • Leone A.M.
        • Vergallo R.
        • Aurigemma C.
        • Buffon A.
        • Romagnoli E.
        • Burzotta F.
        • Trani C.
        • Crea F.
        • Niccoli G.
        Interplay between myocardial bridging and coronary spasm in patients with myocardial ischemia and non-obstructive coronary arteries: pathogenic and prognostic implications.
        J. Am. Heart Assoc. 2021; 10e020535https://doi.org/10.1161/JAHA.120.020535
        • Seitz A.
        • Gardezy J.
        • Pirozzolo G.
        • Probst S.
        • Athanasiadis A.
        • Hill S.
        • Mahrholdt H.
        • Bekeredjian R.
        • Sechtem U.
        • Ong P.
        Long-term follow-up in patients with stable angina and unobstructed coronary arteries undergoing intracoronary acetylcholine testing.
        JACC Cardiovasc. Interv. 2020; 13: 1865-1876https://doi.org/10.1016/j.jcin.2020.05.009
        • Severino P.
        • D’Amato A.
        • Prosperi S.
        • Magnocavallo M.
        • Mariani M.V.
        • Netti L.
        • Birtolo L.I.
        • De Orchi P.
        • Chimenti C.
        • Maestrini V.
        • Miraldi F.
        • Lavalle C.
        • Caputo V.
        • Palmirotta R.
        • Mancone M.
        • Fedele F.
        Potential role of eNOS genetic variants in ischemic heart disease susceptibility and clinical presentation.
        J. Cardiovasc. Dev. Dis. 2021; 8: 116https://doi.org/10.3390/jcdd8090116
        • Kim C.H.
        • Park T.K.
        • Cho S.W.
        • Oh M.S.
        • Lee D.H.
        • Seong C.S.
        • Gwag H.B.
        • Lim A.Y.
        • Yang J.H.
        • Song Y.B.
        • Hahn J.-Y.
        • Choi J.-H.
        • Lee S.H.
        • Gwon H.-C.
        • Ahn J.
        • Carriere K.C.
        • Choi S.-H.
        Impact of different nitrate therapies on long-term clinical outcomes of patients with vasospastic angina: a propensity score-matched analysis.
        Int. J. Cardiol. 2018; 252: 1-5https://doi.org/10.1016/j.ijcard.2017.07.031
        • Takahashi J.
        • Nihei T.
        • Takagi Y.
        • Miyata S.
        • Odaka Y.
        • Tsunoda R.
        • Seki A.
        • Sumiyoshi T.
        • Matsui M.
        • Goto T.
        • Tanabe Y.
        • Sueda S.
        • Momomura S.
        • Yasuda S.
        • Ogawa H.
        • Shimokawa H.
        • Japanese Coronary Spasm Association
        Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association.
        Eur. Heart J. 2015; 36: 228-237https://doi.org/10.1093/eurheartj/ehu313
        • Jansen T.P.J.
        • Konst R.E.
        • de Vos A.
        • Paradies V.
        • Teerenstra S.
        • van den Oord S.C.H.
        • Dimitriu-Leen A.
        • Maas A.H.E.M.
        • Smits P.C.
        • Damman P.
        • van Royen N.
        • Elias-Smale S.E.
        Efficacy of diltiazem to improve coronary vasomotor dysfunction in angina and nonobstructive coronary arteries (ANOCA): results of the EDIT-CMD randomized clinical trial.
        JACC Cardiovasc. Imaging. 2022; (S1936878X22001772)https://doi.org/10.1016/j.jcmg.2022.03.012
        • Ford T.J.
        • Stanley B.
        • Good R.
        • Rocchiccioli P.
        • McEntegart M.
        • Watkins S.
        • Eteiba H.
        • Shaukat A.
        • Lindsay M.
        • Robertson K.
        • Hood S.
        • McGeoch R.
        • McDade R.
        • Yii E.
        • Sidik N.
        • McCartney P.
        • Corcoran D.
        • Collison D.
        • Rush C.
        • McConnachie A.
        • Touyz R.M.
        • Oldroyd K.G.
        • Berry C.
        Stratified medical therapy using invasive coronary function testing in angina.
        J. Am. Coll. Cardiol. 2018; 72: 2841-2855https://doi.org/10.1016/j.jacc.2018.09.006