Angiogenic CD34 Stem Cell Therapy in Coronary Microvascular Repair-A Systematic Review

Balaj Rai, Janki Shukla, Timothy D Henry, Odayme Quesada, Balaj Rai, Janki Shukla, Timothy D Henry, Odayme Quesada

Abstract

Ischemia with non-obstructive coronary arteries (INOCA) is an increasingly recognized disease, with a prevalence of 3 to 4 million individuals, and is associated with a higher risk of morbidity, mortality, and a worse quality of life. Persistent angina in many patients with INOCA is due to coronary microvascular dysfunction (CMD), which can be difficult to diagnose and treat. A coronary flow reserve <2.5 is used to diagnose endothelial-independent CMD. Antianginal treatments are often ineffective in endothelial-independent CMD and thus novel treatment modalities are currently being studied for safety and efficacy. CD34+ cell therapy is a promising treatment option for these patients, as it has been shown to promote vascular repair and enhance angiogenesis in the microvasculature. The resulting restoration of the microcirculation improves myocardial tissue perfusion, resulting in the recovery of coronary microvascular function, as evidenced by an improvement in coronary flow reserve. A pilot study in INOCA patients with endothelial-independent CMD and persistent angina, treated with autologous intracoronary CD34+ stem cells, demonstrated a significant improvement in coronary flow reserve, angina frequency, Canadian Cardiovascular Society class, and quality of life (ESCaPE-CMD, NCT03508609). This work is being further evaluated in the ongoing FREEDOM (NCT04614467) placebo-controlled trial.

Keywords: CD34 stem cell therapy; coronary microvascular dysfunction; ischemia with non-obstructive coronary arteries; refractory angina.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CD34+ cell therapy for patients with obstructive coronary artery disease and refractory angina. Results from the 2018 meta-analysis of three consecutive randomized, double-blinded, placebo-controlled trials in patients with obstructive coronary artery disease and Canadian Cardiovascular Society class 3–4 refractory angina showed that a single intracoronary infusion of autologous CD34+ cells significantly improved total exercise time, decreased angina frequency, and decreased all-cause mortality.
Figure 2
Figure 2
Diagnosis and treatment of coronary microvascular dysfunction.
Figure 3
Figure 3
CD34+ cell therapy for patients with coronary microvascular dysfunction and refractory angina with no obstructive coronary artery disease. Results from the phase 1 ESCaPE-CMD trial (NCT03508609) showed that a single intracoronary infusion of autologous CD34+ cells in patients with coronary microvascular dysfunction and refractory angina with no obstructive coronary artery disease significantly improved coronary flow reserve, decreased angina frequency, and improved quality of life at 6 months.
Figure 4
Figure 4
Trial design of the CD34+ cell therapy FREEDOM trial. The FREEDOM trial (NCT04614467) is a randomized, double-blinded, placebo-controlled trial of CD34+ cell therapy for patients with coronary microvascular dysfunction and refractory angina with no obstructive coronary artery disease.

References

    1. Bairey Merz C.N., Pepine C.J., Walsh M.N., Fleg J.L. Ischemia and No Obstructive Coronary Artery Disease (INOCA): Developing Evidence-Based Therapies and Research Agenda for the Next Decade. Circulation. 2017;135:1075–1092. doi: 10.1161/CIRCULATIONAHA.116.024534.
    1. Widmer R.J., Samuels B., Samady H., Price M.J., Jeremias A., Anderson R.D., Jaffer F.A., Escaned J., Davies J., Prasad M., et al. The functional assessment of patients with non-obstructive coronary artery disease: Expert review from an international microcirculation working group. EuroIntervention. 2019;14:1694–1702. doi: 10.4244/EIJ-D-18-00982.
    1. Kunadian V., Chieffo A., Camici P.G., Berry C., Escaned J., Maas A., Prescott E., Karam N., Appelman Y., Fraccaro C., et al. 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. EuroIntervention. 2021;16:1049–1069. doi: 10.4244/EIJY20M07_01.
    1. Jespersen L., Hvelplund A., Abildstrøm S.Z., Pedersen F., Galatius S., Madsen J.K., Jørgensen E., Kelbæk H., Prescott E. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur. Heart J. 2012;33:734–744. doi: 10.1093/eurheartj/ehr331.
    1. 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;8:1445–1453. doi: 10.1016/j.jcin.2015.06.017.
    1. Recio-Mayoral A., Mason J.C., Kaski J.C., Rubens M.B., Harari O.A., Camici P.G. Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease. Eur. Heart J. 2009;30:1837–1843. doi: 10.1093/eurheartj/ehp205.
    1. Ong P., Camici P.G., Beltrame J.F., Crea F., Shimokawa H., Sechtem U., Kaski J.C., Bairey Merz C.N., Coronary Vasomotion Disorders International Study Group International standardization of diagnostic criteria for microvascular angina. Int. J. Cardiol. 2018;250:16–20. doi: 10.1016/j.ijcard.2017.08.068.
    1. Shaw L.J., Shaw R.E., Merz C.N., Brindis R.G., Klein L.W., Nallamothu B., Douglas P.S., Krone R.J., McKay C.R., Block P.C., et al. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in-hospital mortality in the American College of Cardiology-National Cardiovascular Data Registry. Circulation. 2008;117:1787–1801. doi: 10.1161/CIRCULATIONAHA.107.726562.
    1. Reis S.E., Holubkov R., Lee J.S., Sharaf B., Reichek N., Rogers W.J., Walsh E.G., Fuisz A.R., Kerensky R., Detre K.M., et al. Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women’s Ischemia Syndrome Evaluation (WISE) study. J. Am. Coll. Cardiol. 1999;33:1469–1475. doi: 10.1016/S0735-1097(99)00072-8.
    1. Reis S.E., Holubkov R., Conrad Smith A.J., Kelsey S.F., Sharaf B.L., Reichek N., Rogers W.J., Merz C.N., Sopko G., Pepine C.J., et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: Results from the NHLBI WISE study. Am. Heart J. 2001;141:735–741. doi: 10.1067/mhj.2001.114198.
    1. Pepine C.J., Anderson R.D., Sharaf B.L., Reis S.E., Smith K.M., Handberg E.M., Johnson B.D., Sopko G., Bairey Merz C.N. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study. J. Am. Coll. Cardiol. 2010;55:2825–2832. doi: 10.1016/j.jacc.2010.01.054.
    1. Sietsema W.K., Kawamoto A., Takagi H., Losordo D.W. Autologous CD34+ Cell Therapy for Ischemic Tissue Repair. Circ. J. 2019;83:1422–1430. doi: 10.1253/circj.CJ-19-0240.
    1. Prasad M., Corban M.T., Henry T.D., Dietz A.B., Lerman L.O., Lerman A. Promise of autologous CD34+ stem/progenitor cell therapy for treatment of cardiovascular disease. Cardiovasc. Res. 2020;116:1424–1433. doi: 10.1093/cvr/cvaa027.
    1. Asahara T., Murohara T., Sullivan A., Silver M., van der Zee R., Li T., Witzenbichler B., Schatteman G., Isner J.M. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–967. doi: 10.1126/science.275.5302.964.
    1. Losordo D.W., Schatz R.A., White C.J., Udelson J.E., Veereshwarayya V., Durgin M., Poh K.K., Weinstein R., Kearney M., Chaudhry M., et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: A phase I/IIa double-blind, randomized controlled trial. Circulation. 2007;115:3165–3172. doi: 10.1161/CIRCULATIONAHA.106.687376.
    1. Losordo D.W., Henry T.D., Davidson C., Sup Lee J., Costa M.A., Bass T., Mendelsohn F., Fortuin F.D., Pepine C.J., Traverse J.H., et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ. Res. 2011;109:428–436. doi: 10.1161/CIRCRESAHA.111.245993.
    1. Henry T.D., Schaer G.L., Traverse J.H., Povsic T.J., Davidson C., Lee J.S., Costa M.A., Bass T., Mendelsohn F., Fortuin F.D., et al. Autologous CD34(+) Cell Therapy for Refractory Angina: 2-Year Outcomes From the ACT34-CMI Study. Cell Transpl. 2016;25:1701–1711. doi: 10.3727/096368916X691484.
    1. Povsic T.J., Henry T.D., Traverse J.H., Fortuin F.D., Schaer G.L., Kereiakes D.J., Schatz R.A., Zeiher A.M., White C.J., Stewart D.J., et al. The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34(+) Cell Administration in Patients With Refractory Angina. Jacc. Cardiovasc. Interv. 2016;9:1576–1585. doi: 10.1016/j.jcin.2016.05.003.
    1. Henry T.D., Losordo D.W., Traverse J.H., Schatz R.A., Jolicoeur E.M., Schaer G.L., Clare R., Chiswell K., White C.J., Fortuin F.D., et al. Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: A patient-level pooled analysis of randomized double-blinded trials. Eur. Heart J. 2018;39:2208–2216. doi: 10.1093/eurheartj/ehx764.
    1. Quyyumi A.A., Vasquez A., Kereiakes D.J., Klapholz M., Schaer G.L., Abdel-Latif A., Frohwein S., Henry T.D., Schatz R.A., Dib N., et al. PreSERVE-AMI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intracoronary Administration of Autologous CD34+ Cells in Patients With Left Ventricular Dysfunction Post STEMI. Circ. Res. 2017;120:324–331. doi: 10.1161/CIRCRESAHA.115.308165.
    1. Henry T.D., Noel Bairey Merz C., Wei J., Corban M.T., Quesada O., Joung S., Kotynski C.L., Wang J., Lewis M., Schumacher A.M., et al. CD34+ stem cell therapy increases coronary flow reserve and reduces angina in patients with coronary microvascular dysfunction. Circ. Cardiovasc. Interv. 2021 under review.
    1. Roscoe R.A., Rybka W.B., Winkelstein A., Houston A.M., Kiss J.E. Enumeration of CD34+ hematopoietic stem cells for reconstitution following myeloablative therapy. Cytometry. 1994;16:74–79. doi: 10.1002/cyto.990160111.
    1. Yoshioka T., Ageyama N., Shibata H., Yasu T., Misawa Y., Takeuchi K., Matsui K., Yamamoto K., Terao K., Shimada K., et al. Repair of infarcted myocardium mediated by transplanted bone marrow-derived CD34+ stem cells in a nonhuman primate model. Stem Cells. 2005;23:355–364. doi: 10.1634/stemcells.2004-0200.
    1. Mackie A.R., Losordo D.W. CD34-positive stem cells: In the treatment of heart and vascular disease in human beings. Tex. Heart Inst. J. 2011;38:474–485.
    1. Schatteman G.C., Hanlon H.D., Jiao C., Dodds S.G., Christy B.A. Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. J. Clin. Investig. 2000;106:571–578. doi: 10.1172/JCI9087.
    1. Li S., Zhou B., Han Z.C. Therapeutic neovascularization by transplantation of mobilized peripheral blood mononuclear cells for limb ischemia. A comparison between CD34+ and CD34- mononuclear cells. Thromb. Haemost. 2006;95:301–311. doi: 10.1160/TH05-06-0442.
    1. Madeddu P., Emanueli C., Pelosi E., Salis M.B., Cerio A.M., Bonanno G., Patti M., Stassi G., Condorelli G., Peschle C. Transplantation of low dose CD34+KDR+ cells promotes vascular and muscular regeneration in ischemic limbs. FASEB J. 2004;18:1737–1739. doi: 10.1096/fj.04-2192fje.
    1. Kocher A.A., Schuster M.D., Szabolcs M.J., Takuma S., Burkhoff D., Wang J., Homma S., Edwards N.M., Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat. Med. 2001;7:430–436. doi: 10.1038/86498.
    1. Murohara T., Ikeda H., Duan J., Shintani S., Sasaki K., Eguchi H., Onitsuka I., Matsui K., Imaizumi T. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J. Clin. Investig. 2000;105:1527–1536. doi: 10.1172/JCI8296.
    1. Majka M., Janowska-Wieczorek A., Ratajczak J., Ehrenman K., Pietrzkowski Z., Kowalska M.A., Gewirtz A.M., Emerson S.G., Ratajczak M.Z. Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood. 2001;97:3075–3085. doi: 10.1182/blood.V97.10.3075.
    1. Ohtake T., Mochida Y., Ishioka K., Oka M., Maesato K., Moriya H., Hidaka S., Higashide S., Ioji T., Fujita Y., et al. Autologous Granulocyte Colony-Stimulating Factor-Mobilized Peripheral Blood CD34 Positive Cell Transplantation for Hemodialysis Patients with Critical Limb Ischemia: A Prospective Phase II Clinical Trial. Stem Cells Transl. Med. 2018;7:774–782. doi: 10.1002/sctm.18-0104.
    1. Kawamoto A., Fujita Y., Sietsema W.K., Wang J., Takagi H., Losordo D.W. Design of a potentially registrational study of sakigake-designated GCSF-mobilized autologous CD34 cell (CLBS12) therapy of no-option critical limb ischemia including arteriosclerosis obliterans and buerger’s disease. Cytotherapy. 2020;22:S61. doi: 10.1016/j.jcyt.2020.03.088.
    1. Vrtovec B., Poglajen G., Lezaic L., Sever M., Domanovic D., Cernelc P., Socan A., Schrepfer S., Torre-Amione G., Haddad F., et al. Effects of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ. Res. 2013;112:165–173. doi: 10.1161/CIRCRESAHA.112.276519.
    1. Banerjee S., Bentley P., Hamady M., Marley S., Davis J., Shlebak A., Nicholls J., Williamson D.A., Jensen S.L., Gordon M., et al. Intra-Arterial Immunoselected CD34+ Stem Cells for Acute Ischemic Stroke. Stem Cells Transl. Med. 2014;3:1322–1330. doi: 10.5966/sctm.2013-0178.
    1. Sargento-Freitas J., Pereira A., Gomes A., Amorim P., Matos T., Cardoso C.M.P., Silva F., Santo G.C., Nunes C., Galego O., et al. STROKE34 Study Protocol: A Randomized Controlled Phase IIa Trial of Intra-Arterial CD34+ Cells in Acute Ischemic Stroke. Front. Neurol. 2018;9:302. doi: 10.3389/fneur.2018.00302.
    1. Johnson G.L., Henry T.D., Povsic T.J., Losordo D.W., Garberich R.F., Stanberry L.I., Strauss C.E., Traverse J.H. CD34(+) cell therapy significantly reduces adverse cardiac events, health care expenditures, and mortality in patients with refractory angina. Stem Cells Transl. Med. 2020;9:1147–1152. doi: 10.1002/sctm.20-0046.
    1. Wang S., Cui J., Peng W., Lu M. Intracoronary autologous CD34+ stem cell therapy for intractable angina. Cardiology. 2010;117:140–147. doi: 10.1159/000320217.
    1. Sorop O., Merkus D., de Beer V.J., Houweling B., Pistea A., McFalls E.O., Boomsma F., van Beusekom H.M., van der Giessen W.J., VanBavel E., et al. Functional and structural adaptations of coronary microvessels distal to a chronic coronary artery stenosis. Circ. Res. 2008;102:795–803. doi: 10.1161/CIRCRESAHA.108.172528.
    1. Severino P., D’Amato A., Pucci M., Infusino F., Adamo F., Birtolo L.I., Netti L., Montefusco G., Chimenti C., Lavalle C., et al. Ischemic Heart Disease Pathophysiology Paradigms Overview: From Plaque Activation to Microvascular Dysfunction. Int. J. Mol. Sci. 2020;21:8118. doi: 10.3390/ijms21218118.
    1. Taqueti V.R., Hachamovitch R., Murthy V.L., Naya M., Foster C.R., Hainer J., Dorbala S., Blankstein R., Di Carli M.F. Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization. Circulation. 2015;131:19–27. doi: 10.1161/CIRCULATIONAHA.114.011939.
    1. Khuddus M.A., Pepine C.J., Handberg E.M., Bairey Merz C.N., Sopko G., Bavry A.A., Denardo S.J., McGorray S.P., Smith K.M., Sharaf B.L., et al. An intravascular ultrasound analysis in women experiencing chest pain in the absence of obstructive coronary artery disease: A substudy from the National Heart, Lung and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) J. Interv. Cardiol. 2010;23:511–519. doi: 10.1111/j.1540-8183.2010.00598.x.
    1. Gulati M., Cooper-DeHoff R.M., McClure C., Johnson B.D., Shaw L.J., Handberg E.M., Zineh I., Kelsey S.F., Arnsdorf M.F., Black H.R., et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: A report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch. Intern. Med. 2009;169:843–850. doi: 10.1001/archinternmed.2009.50.
    1. Taqueti V.R., Shaw L.J., Cook N.R., Murthy V.L., Shah N.R., Foster C.R., Hainer J., Blankstein R., Dorbala S., Di Carli M.F. Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography Is Associated With Severely Impaired Coronary Flow Reserve, Not Obstructive Disease. Circulation. 2017;135:566–577. doi: 10.1161/CIRCULATIONAHA.116.023266.
    1. Smith S.M., Huo T., Delia Johnson B., Bittner V., Kelsey S.F., Vido Thompson D., Noel Bairey Merz C., Pepine C.J., Cooper-Dehoff R.M. Cardiovascular and mortality risk of apparent resistant hypertension in women with suspected myocardial ischemia: A report from the NHLBI-sponsored WISE Study. J. Am. Heart Assoc. 2014;3:e000660. doi: 10.1161/JAHA.113.000660.
    1. Di Carli M.F., Janisse J., Grunberger G., Ager J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J. Am. Coll. Cardiol. 2003;41:1387–1393. doi: 10.1016/S0735-1097(03)00166-9.
    1. Wei J., Nelson M.D., Szczepaniak E.W., Smith L., Mehta P.K., Thomson L.E., Berman D.S., Li D., Bairey Merz C.N., Szczepaniak L.S. Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women. Am. J. Physiol. Heart Circ. Physiol. 2016;310:H14–H19. doi: 10.1152/ajpheart.00612.2015.
    1. Kaufmann P.A., Gnecchi-Ruscone T., Schäfers K.P., Lüscher T.F., Camici P.G. Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia. J. Am. Coll. Cardiol. 2000;36:103–109. doi: 10.1016/S0735-1097(00)00697-5.
    1. Vitiello L., Spoletini I., Gorini S., Pontecorvo L., Ferrari D., Ferraro E., Stabile E., Caprio M., la Sala A. Microvascular inflammation in atherosclerosis. Int. J. Cardiol. Metab. Endocr. 2014;3:1–7. doi: 10.1016/j.ijcme.2014.03.002.
    1. Taqueti V.R., Everett B.M., Murthy V.L., Gaber M., Foster C.R., Hainer J., Blankstein R., Dorbala S., Di Carli M.F. Interaction of impaired coronary flow reserve and cardiomyocyte injury on adverse cardiovascular outcomes in patients without overt coronary artery disease. Circulation. 2015;131:528–535. doi: 10.1161/CIRCULATIONAHA.114.009716.
    1. Samim A., Nugent L., Mehta P.K., Shufelt C., Bairey Merz C.N. Treatment of angina and microvascular coronary dysfunction. Curr. Treat. Options. Cardiovasc. Med. 2010;12:355–364. doi: 10.1007/s11936-010-0083-8.
    1. Harris K.F., Matthews K.A. Interactions between autonomic nervous system activity and endothelial function: A model for the development of cardiovascular disease. Psychosom. Med. 2004;66:153–164. doi: 10.1097/01.psy.0000116719.95524.e2.
    1. Mygind N.D., Michelsen M.M., Pena A., Frestad D., Dose N., Aziz A., Faber R., Host N., Gustafsson I., Hansen P.R., et al. Coronary Microvascular Function and Cardiovascular Risk Factors in Women with Angina Pectoris and No Obstructive Coronary Artery Disease: The iPOWER Study. J. Am. Heart Assoc. 2016;5:e003064. doi: 10.1161/JAHA.115.003064.
    1. Taqueti V.R., Di Carli M.F. Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2018;72:2625–2641. doi: 10.1016/j.jacc.2018.09.042.
    1. Feher A., Sinusas A.J. Quantitative Assessment of Coronary Microvascular Function: Dynamic Single-Photon Emission Computed Tomography, Positron Emission Tomography, Ultrasound, Computed Tomography, and Magnetic Resonance Imaging. Circ. Cardiovasc. Imaging. 2017;10 doi: 10.1161/CIRCIMAGING.117.006427.
    1. Murthy V.L., Naya M., Taqueti V.R., Foster C.R., Gaber M., Hainer J., Dorbala S., Blankstein R., Rimoldi O., Camici P.G., et al. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation. 2014;129:2518–2527. doi: 10.1161/CIRCULATIONAHA.113.008507.
    1. Thomson L.E., Wei J., Agarwal M., Haft-Baradaran A., Shufelt C., Mehta P.K., Gill E.B., Johnson B.D., Kenkre T., Handberg E.M., et al. Cardiac magnetic resonance myocardial perfusion reserve index is reduced in women with coronary microvascular dysfunction. A National Heart, Lung, and Blood Institute-sponsored study from the Women’s Ischemia Syndrome Evaluation. Circ. Cardiovasc. Imaging. 2015;8 doi: 10.1161/CIRCIMAGING.114.002481.
    1. Doyle M., Weinberg N., Pohost G.M., Bairey Merz C.N., Shaw L.J., Sopko G., Fuisz A., Rogers W.J., Walsh E.G., Johnson B.D., et al. Prognostic value of global MR myocardial perfusion imaging in women with suspected myocardial ischemia and no obstructive coronary disease: Results from the NHLBI-sponsored WISE (Women’s Ischemia Syndrome Evaluation) study. Jacc. Cardiovasc. Imaging. 2010;3:1030–1036. doi: 10.1016/j.jcmg.2010.07.008.
    1. Knuuti J., Wijns W., Saraste A., Capodanno D., Barbato E., Funck-Brentano C., Prescott E., Storey R.F., Deaton C., Cuisset T., et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur. Heart J. 2020;41:407–477. doi: 10.1093/eurheartj/ehz425.
    1. Ford T.J., Stanley B., Good R., Rocchiccioli P., McEntegart M., Watkins S., Eteiba H., Shaukat A., Lindsay M., Robertson K., et al. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. J. Am. Coll. Cardiol. 2018;72:2841–2855. doi: 10.1016/j.jacc.2018.09.006.
    1. Ludmer P.L., Selwyn A.P., Shook T.L., Wayne R.R., Mudge G.H., Alexander R.W., Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N. Engl. J. Med. 1986;315:1046–1051. doi: 10.1056/NEJM198610233151702.
    1. Fearon W.F., Kobayashi Y. Invasive Assessment of the Coronary Microvasculature: The Index of Microcirculatory Resistance. Circ. Cardiovasc. Interv. 2017;10:e005361. doi: 10.1161/CIRCINTERVENTIONS.117.005361.
    1. Sheikh A.R., Zeitz C.J., Rajendran S., Di Fiore D.P., Tavella R., Beltrame J.F. Clinical and coronary haemodynamic determinants of recurrent chest pain in patients without obstructive coronary artery diseas-A pilot study. Int. J. Cardiol. 2018;267:16–21. doi: 10.1016/j.ijcard.2018.04.077.
    1. Neumann F.J., Sousa-Uva M., Ahlsson A., Alfonso F., Banning A.P., Benedetto U., Byrne R.A., Collet J.P., Falk V., Head S.J., et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur. Heart J. 2019;40:87–165. doi: 10.1093/eurheartj/ehy394.
    1. Beltrame J.F., Crea F., Kaski J.C., Ogawa H., Ong P., Sechtem U., Shimokawa H., Bairey Merz C.N., Coronary Vasomotion Disorders International Study Group International standardization of diagnostic criteria for vasospastic angina. Eur. Heart J. 2017;38:2565–2568. doi: 10.1093/eurheartj/ehv351.
    1. Suda A., Takahashi J., Hao K., Kikuchi Y., Shindo T., Ikeda S., Sato K., Sugisawa J., Matsumoto Y., Miyata S., et al. Coronary Functional Abnormalities in Patients with Angina and Nonobstructive Coronary Artery Disease. J. Am. Coll. Cardiol. 2019;74:2350–2360. doi: 10.1016/j.jacc.2019.08.1056.
    1. Jespersen L., Abildstrom S.Z., Hvelplund A., Prescott E. Persistent angina: Highly prevalent and associated with long-term anxiety, depression, low physical functioning, and quality of life in stable angina pectoris. Clin. Res. Cardiol. 2013;102:571–581. doi: 10.1007/s00392-013-0568-z.
    1. Brainin P., Frestad D., Prescott E. The prognostic value of coronary endothelial and microvascular dysfunction in subjects with normal or non-obstructive coronary artery disease: A systematic review and meta-analysis. Int. J. Cardiol. 2018;254:1–9. doi: 10.1016/j.ijcard.2017.10.052.
    1. Suhrs H.E., Michelsen M.M., Prescott E. Treatment strategies in coronary microvascular dysfunction: A systematic review of interventional studies. Microcirculation. 2019;26:e12430. doi: 10.1111/micc.12430.
    1. Williams B., Mancia G., Spiering W., Rosei E.A., Azizi M., Burnier M., Clement D.L., Coca A., de Simone G., Dominiczak A., et al. [2018 ESC/ESH Guidelines for the management of arterial hypertension] Kardiol. Pol. 2019;77:71–159. doi: 10.5603/KP.2019.0018.
    1. Pauly D.F., Johnson B.D., Anderson R.D., Handberg E.M., Smith K.M., Cooper-DeHoff R.M., Sopko G., Sharaf B.M., Kelsey S.F., Merz C.N., et al. In women with symptoms of cardiac ischemia, nonobstructive coronary arteries, and microvascular dysfunction, angiotensin-converting enzyme inhibition is associated with improved microvascular function: A double-blind randomized study from the National Heart, Lung and Blood Institute Women’s Ischemia Syndrome Evaluation (WISE) Am. Heart J. 2011;162:678–684. doi: 10.1016/j.ahj.2011.07.011.
    1. Zhang X., Li Q., Zhao J., Li X., Sun X., Yang H., Wu Z., Yang J. Effects of combination of statin and calcium channel blocker in patients with cardiac syndrome X. Coron. Artery. Dis. 2014;25:40–44. doi: 10.1097/MCA.0000000000000054.
    1. Task Force M., Montalescot G., Sechtem U., Achenbach S., Andreotti F., Arden C., Budaj A., Bugiardini R., Crea F., Cuisset T., et al. 2013 ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur. Heart J. 2013;34:2949–3003. doi: 10.1093/eurheartj/eht296.
    1. Wei J., Shufelt C., Bairey Merz C.N. Women’s health: Making cardiovascular disease real. Curr. Opin. Cardiol. 2018;33:506–513. doi: 10.1097/HCO.0000000000000544.
    1. Ford T.J., Berry C. How to Diagnose and Manage Angina Without Obstructive Coronary Artery Disease: Lessons from the British Heart Foundation CorMicA Trial. Interv. Cardiol. 2019;14:76–82. doi: 10.15420/icr.2019.04.R1.
    1. Russo G., Di Franco A., Lamendola P., Tarzia P., Nerla R., Stazi A., Villano A., Sestito A., Lanza G.A., Crea F. Lack of effect of nitrates on exercise stress test results in patients with microvascular angina. Cardiovasc. Drugs. 2013;27:229–234. doi: 10.1007/s10557-013-6439-z.
    1. Bairey Merz C.N., Handberg E.M., Shufelt C.L., Mehta P.K., Minissian M.B., Wei J., Thomson L.E., Berman D.S., Shaw L.J., Petersen J.W., et al. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): Impact on angina and myocardial perfusion reserve. Eur. Heart J. 2016;37:1504–1513. doi: 10.1093/eurheartj/ehv647.
    1. Guarini G., Huqi A., Morrone D., Capozza P., Todiere G., Marzilli M. Pharmacological approaches to coronary microvascular dysfunction. Pharm. Ther. 2014;144:283–302. doi: 10.1016/j.pharmthera.2014.06.008.
    1. Villano A., Di Franco A., Nerla R., Sestito A., Tarzia P., Lamendola P., Di Monaco A., Sarullo F.M., Lanza G.A., Crea F. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am. J. Cardiol. 2013;112:8–13. doi: 10.1016/j.amjcard.2013.02.045.
    1. Yesildag O., Yazici M., Yilmaz O., Ucar R., Sagkan O. The effect of aminophylline infusion on the exercise capacity in patients with syndrome X. Acta Cardiol. 1999;54:335–337.
    1. Shi J., Wei L. Rho kinases in cardiovascular physiology and pathophysiology: The effect of fasudil. J. Cardiovasc. Pharm. 2013;62:341–354. doi: 10.1097/FJC.0b013e3182a3718f.
    1. Palmer R.M., Ashton D.S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333:664–666. doi: 10.1038/333664a0.
    1. Asbury E.A., Kanji N., Ernst E., Barbir M., Collins P. Autogenic training to manage symptomology in women with chest pain and normal coronary arteries. Menopause. 2009;16:60–65. doi: 10.1097/gme.0b013e318184762e.
    1. Cannon R.O., 3rd, Quyyumi A.A., Mincemoyer R., Stine A.M., Gracely R.H., Smith W.B., Geraci M.F., Black B.C., Uhde T.W., Waclawiw M.A., et al. Imipramine in patients with chest pain despite normal coronary angiograms. N. Engl. J. Med. 1994;330:1411–1417. doi: 10.1056/NEJM199405193302003.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe