Systemic microvascular dysfunction in microvascular and vasospastic angina

Thomas J Ford, Paul Rocchiccioli, Richard Good, Margaret McEntegart, Hany Eteiba, Stuart Watkins, Aadil Shaukat, Mitchell Lindsay, Keith Robertson, Stuart Hood, Eric Yii, Novalia Sidik, Adam Harvey, Augusto C Montezano, Elisabeth Beattie, Laura Haddow, Keith G Oldroyd, Rhian M Touyz, Colin Berry, Thomas J Ford, Paul Rocchiccioli, Richard Good, Margaret McEntegart, Hany Eteiba, Stuart Watkins, Aadil Shaukat, Mitchell Lindsay, Keith Robertson, Stuart Hood, Eric Yii, Novalia Sidik, Adam Harvey, Augusto C Montezano, Elisabeth Beattie, Laura Haddow, Keith G Oldroyd, Rhian M Touyz, Colin Berry

Abstract

Aims: Coronary microvascular dysfunction and/or vasospasm are potential causes of ischaemia in patients with no obstructive coronary artery disease (INOCA). We tested the hypothesis that these patients also have functional abnormalities in peripheral small arteries.

Methods and results: Patients were prospectively enrolled and categorised as having microvascular angina (MVA), vasospastic angina (VSA) or normal control based on invasive coronary artery function tests incorporating probes of endothelial and endothelial-independent function (acetylcholine and adenosine). Gluteal biopsies of subcutaneous fat were performed in 81 subjects (62 years, 69% female, 59 MVA, 11 VSA, and 11 controls). Resistance arteries were dissected enabling study using wire myography. Maximum relaxation to ACh (endothelial function) was reduced in MVA vs. controls [median 77.6 vs. 98.7%; 95% confidence interval (CI) of difference 2.3-38%; P = 0.0047]. Endothelium-independent relaxation [sodium nitroprusside (SNP)] was similar between all groups. The maximum contractile response to endothelin-1 (ET-1) was greater in MVA (median 121%) vs. controls (100%; 95% CI of median difference 4.7-45%, P = 0.015). Response to the thromboxane agonist, U46619, was also greater in MVA (143%) vs. controls (109%; 95% CI of difference 13-57%, P = 0.003). Patients with VSA had similar abnormal patterns of peripheral vascular reactivity including reduced maximum relaxation to ACh (median 79.0% vs. 98.7%; P = 0.03) and increased response to constrictor agonists including ET-1 (median 125% vs. 100%; P = 0.02). In all groups, resistance arteries were ≈50-fold more sensitive to the constrictor effects of ET-1 compared with U46619.

Conclusions: Systemic microvascular abnormalities are common in patients with MVA and VSA. These mechanisms may involve ET-1 and were characterized by endothelial dysfunction and enhanced vasoconstriction.

Clinical trial registration: ClinicalTrials.gov registration is NCT03193294.

Figures

Figure 1
Figure 1
(A) Illustrative case of microvascular angina. (B) Gluteal biopsy procedure, dissection of resistance artery, and myography workstation. (A) A 43-year-old female smoker with family history of early cardiovascular disease was referred for invasive angiography with 12 months of typical angina and positive stress ECG. Recruited into British Heart Foundation CorMicA study with findings of non-obstructive atheroma in the left anterior descending coronary artery. Pressure wire assessment confirmed profoundly reduced coronary flow reserve (1.3) but non-obstructive physiology (fractional flow reserve 0.86) and normal index of microvascular resistance with adenosine (index of microcirculatory resistance 18). Acetylcholine testing confirmed microvascular spasm to acetylcholine (reproduction of typical angina, ST segment deviation and <90% epicardial vasoconstriction to acetylcholine. (B) Surgical gluteal skin fat biopsy with dissection of resistance artery under light microscopy. Peripheral resistance arteries were harvested and set-up for our wire myography protocol. The myography tracing shows a cumulative concentration-response curve to dilator agonist acetylcholine. We averaged the relaxation at each concentration compared to baseline confirming reduced maximal relaxation to this probe of endothelial function. Overall this lady was diagnosed with microvascular angina (typical angina, proven coronary microvascular dysfunction) with evidence of widespread peripheral endothelial dysfunction.
Figure 2
Figure 2
(A) Primary endpoint: maximum vasorelaxation to acetylcholine (Emax). (B) Comparison of maximum relaxation to acetylcholine between the three groups. (A) Ranks: the Mann–Whitney U test ranking of microvascular angina vs. control subjects confirming significantly lower maximum vasorelaxation in response to acetylcholine between microvascular angina patients and control subject (median 77.6 vs. 98.7%; 95% confidence interval of difference between medians 2.3–38%; P = 0.0047). (B) Comparison of three groups confirming both microvascular angina subjects (blue circle; acetylcholine Emax 77.6%, n = 48) and vasospastic angina subjects (red triangle; acetylcholine Emax 79%, n = 9) had reduced maximum vasorelaxation to acetylcholine than vs. control subjects (○—white circle, Emax 98.7%, n = 10). Significance P < 0.01 and P = 0.03, respectively using the Kruskal–Wallis test (adjusted for multiple comparisons by controlling the false discovery rate). Each measure represents mean ± 95% confidence intervals for mean in shaded contours from CCRC best-fit. There were no significant differences in maximum relaxation to acetylcholine between microvascular angina and vasospastic angina subjects (P = 0.96).
Figure 3
Figure 3
Cumulative concentration-response curves to dilator agonists. (A) Endothelial function assessed by acetylcholine showing impairment in vasorelaxation in both microvascular angina subjects (blue circle; acetylcholine Emax 77.6%, n = 48; P < 0.01) and vasospastic angina subjects (red triangle; acetylcholine Emax 79%, n = 9; P = 0.03) vs. control subjects (○—white circle, Emax 98.7%, n = 10). No difference in acetylcholine Emax between microvascular angina and vasospastic angina subjects (P = 0.967). Comparison of CCRC fit, P < 0.001. (B) No difference in vasorelaxation to endothelial independent probe, sodium nitroprusside between microvascular angina patients (blue circle, sodium nitroprusside Emax 97%, n = 49), vasospastic angina subjects (red triangle; acetylcholine Emax 99%; n = 10) and control subjects (○—white circle, Emax 98%, n = 10; P = 0.99). Each measure represents mean ± 95% confidence intervals for mean in shaded contours from CCRC best-fit. No difference in response to sodium nitroprusside between the groups, P = 0.4914.
Figure 4
Figure 4
Cumulative concentration-response curves to constrictor agonists. (A) Increased maximum vasoconstriction to endothelin-1 in both microvascular angina subjects (blue circle, endothelin-1 Emax 121%, n = 54; P = 0.03) and vasospastic angina subjects (red triangle, endothelin-1 Emax 125%, n = 11; P = 0.02) vs. control subjects (○—white circle, endothelin-1 Emax 100%, n = 9; P = 0.02). No difference in endothelin-1 Emax between microvascular angina and vasospastic angina subjects (P = 0.397). Comparison of CCRC fit, P < 0.001. (B) Cumulative concentration-response curves to thromboxane analogue, U46619, in both microvascular angina subjects (blue circle, U46619 Emax 143%, n = 54; P = 0.01) and vasospastic angina subjects (red triangle, Emax 141%, n = 10; P = 0.04) vs. control subjects (○—white circle, endothelin-1 Emax 109%, n = 11). No difference in Emax between microvascular angina and vasospastic angina subjects (P = 0.932). Comparison of CCRC fit, P < 0.001. Each measure represents mean ± 95% confidence intervals for mean in shaded contours from CCRC best-fit.
Take home figure
Take home figure
Systemic microvascular dysfunction in microvascular and vasospastic angina.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6284165/bin/ehy529f5.jpg

References

    1. Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL.. Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade. Circulation 2017;135:1075–1092.
    1. Maddox TM, Stanislawski MA, Grunwald GK, Bradley SM, Ho PM, Tsai TT, Patel MR, Sandhu A, Valle J, Magid DJ, Leon B, Bhatt DL, Fihn SD, Rumsfeld JS.. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA 2014;312:1754–1763.
    1. Tavella R, Cutri N, Tucker G, Adams R, Spertus J, Beltrame JF.. Natural history of patients with insignificant coronary artery disease. Eur Heart J Qual Care Clin Outcomes 2016;2:117–124.
    1. Task Force Members Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK, Hulot JS, Marx N, Opie LH, Pfisterer M, Prescott E, Ruschitzka F, Sabate M, Senior R, Taggart DP, van der Wall EE, Vrints CJ ESC Committee for Practice Guidelines Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Document R, Knuuti J, Valgimigli M, Bueno H, Claeys MJ, Donner-Banzhoff N, Erol C, Frank H, Funck-Brentano C, Gaemperli O, Gonzalez-Juanatey JR, Hamilos M, Hasdai D, Husted S, James SK, Kervinen K, Kolh P, Kristensen SD, Lancellotti P, Maggioni AP, Piepoli MF, Pries AR, Romeo F, Ryden L, Simoons ML, Sirnes PA, Steg PG, Timmis A, Wijns W, Windecker S, Yildirir A, Zamorano JL.. 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.
    1. Mohandas R, Segal MS, Huo T, Handberg EM, Petersen JW, Johnson BD, Sopko G, Bairey Merz CN, Pepine CJ.. Renal function and coronary microvascular dysfunction in women with symptoms/signs of ischemia. PLoS One 2015;10:e0125374.
    1. Liew G, Wang JJ, Mitchell P, Wong TY.. Retinal vascular imaging: a new tool in microvascular disease research. Circ Cardiovasc Imaging 2008;1:156–161.
    1. Sun S-S, Shiau Y-C, Tsai S-C, Ho Y-J, Wang J-J, Kao C-H.. Cerebral perfusion in patients with syndrome X: a single photon emission computed tomography study. J Neuroimaging 2001;11:148–152.
    1. Parrinello R, Sestito A, Di Franco A, Russo G, Villano A, Figliozzi S, Nerla R, Tarzia P, Stazi A, Lanza GA, Crea F.. Peripheral arterial function and coronary microvascular function in patients with variant angina. Cardiology 2014;129:20–24.
    1. Rigo F, Pratali L, Pálinkás A, Picano E, Cutaia V, Venneri L, Raviele A.. Coronary flow reserve and brachial artery reactivity in patients with chest pain and “false positive” exercise-induced ST-segment depression. Am J Cardiol 2002;89:1141–1144.
    1. Sainsbury CA, Coleman J, Brady AJ, Connell JM, Hillier C, Petrie JR.. Endothelium-dependent relaxation is resistant to inhibition of nitric oxide synthesis, but sensitive to blockade of calcium-activated potassium channels in essential hypertension. J Hum Hypertens 2007;21:808–814.
    1. Dalzell JR, Seed A, Berry C, Whelan CJ, Petrie MC, Padmanabhan N, Clarke A, Biggerstaff F, Hillier C, McMurray JJ.. Effects of neutral endopeptidase (neprilysin) inhibition on the response to other vasoactive peptides in small human resistance arteries: studies with thiorphan and omapatrilat. Cardiovasc Ther 2014;32:13–18.
    1. Morris ST, McMurray JJ, Spiers A, Jardine AG.. Impaired endothelial function in isolated human uremic resistance arteries. Kidney Int 2001;60:1077–1082.
    1. Ford TJ, Corcoran D, Oldroyd KG, McEntegart M, Rocchiccioli P, Watkins S, Brooksbank K, Padmanabhan S, Sattar N, Briggs A, McConnachie A, Touyz R, Berry C.. Rationale and design of the British Heart Foundation (BHF) Coronary Microvascular Angina (CorMicA) stratified medicine clinical trial. Am Heart J 2018;201:86–94.
    1. Rose G, McCartney P, Reid DD.. Self-administration of a questionnaire on chest pain and intermittent claudication. Br J Prev Soc Med 1977;31:42–48.
    1. Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, Shimokawa H, Bairey Merz CN; Coronary Vasomotion Disorders International Study Group. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J 2017;38:2565–2568.
    1. Fearon WF, Balsam LB, Farouque HM, Caffarelli AD, Robbins RC, Fitzgerald PJ, Yock PG, Yeung AC.. Novel index for invasively assessing the coronary microcirculation. Circulation 2003;107:3129–3132.
    1. De Bruyne B, Baudhuin T, Melin JA, Pijls NH, Sys SU, Bol A, Paulus WJ, Heyndrickx GR, Wijns W.. Coronary flow reserve calculated from pressure measurements in humans. Validation with positron emission tomography. Circulation 1994;89:1013–1022.
    1. Lee BK, Lim HS, Fearon WF, Yong AS, Yamada R, Tanaka S, Lee DP, Yeung AC, Tremmel JA.. Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease. Circulation 2015;131:1054–1060.
    1. Pijls NHJ, De Bruyne B, Smith L, Aarnoudse W, Barbato E, Bartunek J, Bech GJW, Van De Vosse F.. Coronary thermodilution to assess flow reserve: validation in humans. Circulation 2002;105:2482–2486.
    1. Murthy VL, Naya M, Taqueti VR, Foster CR, Gaber M, Hainer J, Dorbala S, Blankstein R, Rimoldi O, Camici PG, Di Carli MF.. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation 2014;129:2518–2527.
    1. Lerman A, Holmes DR, Bell MR, Garratt KN, Nishimura RA, Burnett JC.. Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. Circulation 1995;92:2426–2431.
    1. Hillier C, Berry C, Petrie MC, O'Dwyer PJ, Hamilton C, Brown A, McMurray J.. Effects of urotensin II in human arteries and veins of varying caliber. Circulation 2001;103:1378–1381.
    1. Tousoulis D, Davies G, Lefroy DC, Haider AW, Crake T.. Variable coronary vasomotor responses to acetylcholine in patients with normal coronary arteriograms: evidence for localised endothelial dysfunction. Heart 1996;75:261–266.
    1. Iantorno M, Weiss RG.. Using advanced noninvasive imaging techniques to probe the links between regional coronary artery endothelial dysfunction and atherosclerosis. Trends Cardiovasc Med 2014;24:149–156.
    1. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 1983;51:606..
    1. Thompson CS, Hakim AM.. Living beyond our physiological means: small vessel disease of the brain is an expression of a systemic failure in arteriolar function: a unifying hypothesis. Stroke 2009;40:e322–e330.
    1. Ong P, Camici PG, Beltrame JF, Crea F, Shimokawa H, Sechtem U, Kaski JC, Bairey Merz CN; Coronary Vasomotion Disorders International Study Group. International standardization of diagnostic criteria for microvascular angina. Int J Cardiol 2018;250:16–20.
    1. Sax FL, Cannon RO, Hanson C, Epstein SE.. Impaired forearm vasodilator reserve in patients with microvascular angina. N Engl J Med 1987;317:1366–1370.
    1. Teragawa H, Kato M, Kurokawa J, Yamagata T, Matsuura H, Chayama K.. Endothelial dysfunction is an independent factor responsible for vasospastic angina. Clin Sci 2001;101:707..
    1. Crea F, Lanza GA.. Treatment of microvascular angina: the need for precision medicine. Eur Heart J 2016;37:1514–1516.
    1. Shimokawa H. 2014 Williams Harvey Lecture: importance of coronary vasomotion abnormalities-from bench to bedside. Eur Heart J 2014;35:3180–3193.
    1. Marinescu MA, Loffler AI, Ouellette M, Smith L, Kramer CM, Bourque JM.. Coronary microvascular dysfunction, microvascular angina, and treatment strategies. JACC Cardiovasc Imaging 2015;8:210–220.
    1. De Ciuceis C, Porteri E, Rizzoni D, Rizzardi N, Paiardi S, Boari GE, Miclini M, Zani F, Muiesan ML, Donato F, Salvetti M, Castellano M, Tiberio GA, Giulini SM, Agabiti Rosei E.. Structural alterations of subcutaneous small-resistance arteries may predict major cardiovascular events in patients with hypertension. Am J Hypertens 2007;20:846–852.
    1. Rizzoni D, Porteri E, Boari GE, De Ciuceis C, Sleiman I, Muiesan ML, Castellano M, Miclini M, Agabiti-Rosei E.. Prognostic significance of small-artery structure in hypertension. Circulation 2003;108:2230–2235.
    1. Spiers A, Padmanabhan N.. A guide to wire myography. Methods Mol Med 2005;108:91–104.
    1. Luksha L, Stenvinkel P, Hammarqvist F, Carrero JJ, Davidge ST, Kublickiene K.. Mechanisms of endothelial dysfunction in resistance arteries from patients with end-stage renal disease. PLoS One 2012;7:e36056.
    1. Wanstall JC, Jeffery TK, Gambino A, Lovren F, Triggle CR.. Vascular smooth muscle relaxation mediated by nitric oxide donors: a comparison with acetylcholine, nitric oxide andnitroxyl ion. Br J Pharmacol 2001;134:463–472.
    1. Newby DE, Flint LL, Fox KA, Boon NA, Webb DJ.. Reduced responsiveness to endothelin-1 in peripheral resistance vessels of patients with syndrome X. J Am Coll Cardiol 1998;31:1585–1590.
    1. Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Luscher TF, Shechter M, Taddei S, Vita JA, Lerman A.. The assessment of endothelial function: from research into clinical practice. Circulation 2012;126:753–767.
    1. Sun H, Mohri M, Shimokawa H, Usui M, Urakami L, Takeshita A.. Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina. J Am Coll Cardiol 2002;39:847–851.
    1. Clempus RE, Griendling KK.. Reactive oxygen species signaling in vascular smooth muscle cells. Cardiovasc Res 2006;71:216–225.
    1. Niccoli G, Scalone G, Crea F.. Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management. Eur Heart J 2015;36:475–481.
    1. Miller D, Waters DD, Warnica W, Szlachcic J, Kreeft J, Théroux P.. Is variant angina the coronary manifestation of a generalized vasospastic disorder? N Engl J Med 1981;304:763–766.
    1. Vanmolkot FH, Van Bortel LM, de Hoon JN.. Altered arterial function in migraine of recent onset. Neurology 2007;68:1563.
    1. Tambe AA, Demany MA, Zimmerman HA, Mascarenhas E.. Angina pectoris and slow flow velocity of dye in coronary arteries–a new angiographic finding. Am Heart J 1972;84:66–71.
    1. Beltrame JF, Limaye SB, Horowitz JD.. The coronary slow flow phenomenon–a new coronary microvascular disorder. Cardiology 2002;97:197–202.
    1. Mohri M, Koyanagi M, Egashira K, Tagawa H, Ichiki T, Shimokawa H, Takeshita A.. Angina pectoris caused by coronary microvascular spasm. Lancet 1998;351:1165–1169.
    1. Aghamohammadzadeh R, Greenstein AS, Yadav R, Jeziorska M, Hama S, Soltani F, Pemberton PW, Ammori B, Malik RA, Soran H, Heagerty AM.. Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity. J Am Coll Cardiol 2013;62:128–135.
    1. Al-Lamee R, Howard JP, Shun-Shin MJ, Thompson D, Dehbi HM, Sen S, Nijjer S, Petraco R, Davies J, Keeble T, Tang K, Malik IS, Cook C, Ahmad Y, Sharp ASP, Gerber R, Baker C, Kaprielian R, Talwar S, Assomull R, Cole G, Keenan NG, Kanaganayagam G, Sehmi J, Wensel R, Harrell FE, Mayet J, Thom SA, Davies JE, Francis DP.. Fractional flow reserve and instantaneous wave-free ratio as predictors of the placebo-controlled response to percutaneous coronary intervention in stable single-vessel coronary artery disease: physiology-stratified analysis of ORBITA. Circulation 2018;138: doi:10.1161/CIRCULATIONAHA.118.033801.
    1. McNair LL, Salamanca DA, Khalil RA.. Endothelin-1 promotes Ca2+ antagonist-insensitive coronary smooth muscle contraction via activation of epsilon-protein kinase C. Hypertension 2004;43:897–904.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する