Coronary Microvascular Function and Cardiovascular Risk Factors in Women With Angina Pectoris and No Obstructive Coronary Artery Disease: The iPOWER Study

Naja Dam Mygind, Marie Mide Michelsen, Adam Pena, Daria Frestad, Nynne Dose, Ahmed Aziz, Rebekka Faber, Nis Høst, Ida Gustafsson, Peter Riis Hansen, Henrik Steen Hansen, C Noel Bairey Merz, Jens Kastrup, Eva Prescott, Naja Dam Mygind, Marie Mide Michelsen, Adam Pena, Daria Frestad, Nynne Dose, Ahmed Aziz, Rebekka Faber, Nis Høst, Ida Gustafsson, Peter Riis Hansen, Henrik Steen Hansen, C Noel Bairey Merz, Jens Kastrup, Eva Prescott

Abstract

Background: The majority of women with angina-like chest pain have no obstructive coronary artery disease when evaluated with coronary angiography. Coronary microvascular dysfunction is a possible explanation and associated with a poor prognosis. This study evaluated the prevalence of coronary microvascular dysfunction and the association with symptoms, cardiovascular risk factors, psychosocial factors, and results from diagnostic stress testing.

Methods and results: After screening 3568 women, 963 women with angina-like chest pain and a diagnostic coronary angiogram without significant coronary artery stenosis (<50%) were consecutively included. Mean age (SD) was 62.1 (9.7). Assessment included demographic and clinical data, blood samples, questionnaires, and transthoracic echocardiography during rest and high-dose dipyridamole (0.84 mg/kg) with measurement of coronary flow velocity reserve (CFVR) by Doppler examination of the left anterior descending coronary artery. CFVR was successfully measured in 919 (95%) women. Median (IQR) CFVR was 2.33 (1.98-2.76), and 241 (26%) had markedly impaired CFVR (<2). In multivariable regression analysis, predictors of impaired CFVR were age (P<0.01), hypertension (P=0.02), current smoking (P<0.01), elevated heart rate (P<0.01), and low high-density lipoprotein cholesterol (P=0.02), but these variables explained only a little of the CFVR variation (r(2)=0.09). CFVR was not associated with chest pain characteristics or results from diagnostic stress testing.

Conclusion: Impaired CFVR was detected in a substantial proportion, which suggests that coronary microvascular dysfunction plays a role in the development of angina pectoris. CFVR was associated with few cardiovascular risk factors, suggesting that CFVR is an independent parameter in the risk evaluation of these women. Symptom characteristics and results from stress testing did not identify individuals with impaired CFVR.

Keywords: angina pectoris; coronary artery disease; echocardiography; microvascular dysfunction; women.

© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Inclusion and exclusion criteria in the iPOWER study.
Figure 2
Figure 2
Measurement of coronary flow velocity. DPV indicates diastolic peak velocity.
Figure 3
Figure 3
Participant flow chart. CAD indicates coronary artery disease; CAG, coronary angiography; CFVR, coronary flow reserve.
Figure 4
Figure 4
Seattle Angina Questionnaire. Higher scores represent higher/better function of each variable in Seattle Angina Questionnaire. *P value from trend‐test (age‐corrected multivariate regression). ‡P value from regression analysis with natural logarithmically transformed CFVR as outcome. CFVR indicates coronary flow velocity reserve.

References

    1. Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, Madsen JK, Jorgensen E, Kelbaek 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.
    1. Jespersen L, Abildstrom SZ, Hvelplund A, Galatius S, Madsen JK, Pedersen F, Hojberg S, Prescott E. Symptoms of angina pectoris increase the probability of disability pension and premature exit from the workforce even in the absence of obstructive coronary artery disease. Eur Heart J. 2013;34:3294–3303.
    1. Jespersen L, Abildstrom SZ, 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.
    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. Pepine CJ, Anderson RD, Sharaf BL, Reis SE, Smith KM, Handberg EM, Johnson BD, Sopko G, Bairey Merz CN. 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.
    1. Sicari R, Rigo F, Cortigiani L, Gherardi S, Galderisi M, Picano E. Additive prognostic value of coronary flow reserve in patients with chest pain syndrome and normal or near‐normal coronary arteries. Am J Cardiol. 2009;103:626–631.
    1. El FG, Sitek A, Guerin B, Kijewski MF, Di Carli MF, Moore SC. Quantitative dynamic cardiac 82Rb PET using generalized factor and compartment analyses. J Nucl Med. 2005;46:1264–1271.
    1. Murthy VL, Naya M, Foster CR, Hainer J, Gaber M, Di CG, Blankstein R, Dorbala S, Sitek A, Pencina MJ, Di Carli MF. Improved cardiac risk assessment with noninvasive measures of coronary flow reserve. Circulation. 2011;124:2215–2224.
    1. Douglas PS, Hoffmann U, Patel MR, Mark DB, Al‐Khalidi HR, Cavanaugh B, Cole J, Dolor RJ, Fordyce CB, Huang M, Khan MA, Kosinski AS, Krucoff MW, Malhotra V, Picard MH, Udelson JE, Velazquez EJ, Yow E, Cooper LS, Lee KL. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med. 2015;372:1291–1300.
    1. Prescott E, Abildstrom SZ, Aziz A, Merz NB, Gustafsson I, Halcox J, Hansen HS, Hansen PR, Kastrup J, Michelsen M, Mygind ND, Ong P, Pena A, Rosengren A, Sechtem U, Sogaard P. Improving diagnosis and treatment of women with angina pectoris and microvascular disease: the iPOWER study design and rationale. Am Heart J. 2014;167:452–458.
    1. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, Bugiardini R, Crea F, Cuisset T, Di MC, 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, 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, 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. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, Douglas PS, Foody JM, Gerber TC, Hinderliter AL, King SB III, Kligfield PD, Krumholz HM, Kwong RY, Lim MJ, Linderbaum JA, Mack MJ, Munger MA, Prager RL, Sabik JF, Shaw LJ, Sikkema JD, Smith CR Jr, Smith SC Jr, Spertus JA, Williams SV. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60:e44–e164.
    1. Spertus JA, Winder JA, Dewhurst TA, Deyo RA, Prodzinski J, McDonell M, Fihn SD. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll Cardiol. 1995;25:333–341.
    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. Lim HE, Shim WJ, Rhee H, Kim SM, Hwang GS, Kim YH, Seo HS, Oh DJ, Ro YM. Assessment of coronary flow reserve with transthoracic Doppler echocardiography: comparison among adenosine, standard‐dose dipyridamole, and high‐dose dipyridamole. J Am Soc Echocardiogr. 2000;13:264–270.
    1. Picano E. Stress Echocardiography. 5th ed Springer‐Verlag Berlin Heidelberg: Springer; 2009.
    1. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, Bugiardini R, Crea F, Cuisset T, Mario C, Feddeira R, Gersh BJ, Gitt AK, Hulot JS, Marx N, Opie LH, Pfisterer M, Prescott E, Ruschitzka F, Sabate M, Senior R, Taggart DP, Wall E, Vrints CJ. 2013 ESC guidelines on the management of stable coronary artery disease‐addenda. 2013:1–32. Available at: . Accessed October 23, 2015.
    1. Graf S, Khorsand A, Gwechenberger M, Novotny C, Kletter K, Sochor H, Pirich C, Maurer G, Porenta G, Zehetgruber M. Typical chest pain and normal coronary angiogram: cardiac risk factor analysis versus PET for detection of microvascular disease. J Nucl Med. 2007;48:175–181.
    1. Cho I, Chang HJ, Sung JM, Pencina MJ, Lin FY, Dunning AM, Achenbach S, Al‐Mallah M, Berman DS, Budoff MJ, Callister TQ, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Maffei E, Cademartiri F, Kaufmann P, Shaw LJ, Raff GL, Chinnaiyan KM, Villines TC, Cheng V, Nasir K, Gomez M, Min JK. Coronary computed tomographic angiography and risk of all‐cause mortality and nonfatal myocardial infarction in subjects without chest pain syndrome from the CONFIRM Registry (coronary CT angiography evaluation for clinical outcomes: an international multicenter registry). Circulation. 2012;126:304–313.
    1. Weintraub WS, Spertus JA, Kolm P, Maron DJ, Zhang Z, Jurkovitz C, Zhang W, Hartigan PM, Lewis C, Veledar E, Bowen J, Dunbar SB, Deaton C, Kaufman S, O'Rourke RA, Goeree R, Barnett PG, Teo KK, Boden WE, Mancini GB. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med. 2008;359:677–687.
    1. Sade LE, Eroglu S, Bozbas H, Ozbicer S, Hayran M, Haberal A, Muderrisoglu H. Relation between epicardial fat thickness and coronary flow reserve in women with chest pain and angiographically normal coronary arteries. Atherosclerosis. 2009;204:580–585.
    1. Reis SE, Holubkov R, Conrad Smith AJ, Kelsey SF, Sharaf BL, Reichek N, Rogers WJ, Merz CN, Sopko G, Pepine CJ. 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.
    1. Sara JD, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, Lerman A. Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease. JACC Cardiovasc Interv. 2015;8:1445–1453.
    1. Wessel TR, Arant CB, McGorray SP, Sharaf BL, Reis SE, Kerensky RA, von Mering GO, Smith KM, Pauly DF, Handberg EM, Mankad S, Olson MB, Johnson BD, Merz CN, Sopko G, Pepine CJ. Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE). Clin Cardiol. 2007;30:69–74.
    1. The National Institute of Public Health . The National Health Interview Surveys. 2013. Available at: . Accessed April 29, 2015.
    1. Lee DH, Youn HJ, Choi YS, Park CS, Park JH, Jeon HK, Kim JH. Coronary flow reserve is a comprehensive indicator of cardiovascular risk factors in subjects with chest pain and normal coronary angiogram. Circ J. 2010;74:1405–1414.
    1. Tuccillo B, Accadia M, Rumolo S, Iengo R, D'Andrea A, Granata G, Sacra C, Guarini P, Al‐Kebsi M, De MM, Ascione L. Factors predicting coronary flow reserve impairment in patients evaluated for chest pain: an ultrasound study. J Cardiovasc Med (Hagerstown). 2008;9:251–255.
    1. Ahmari SA, Bunch TJ, Modesto K, Stussy V, Dichak A, Seward JB, Pellikka PA, Chandrasekaran K. Impact of individual and cumulative coronary risk factors on coronary flow reserve assessed by dobutamine stress echocardiography. Am J Cardiol. 2008;101:1694–1699.
    1. Tona F, Serra R, Di AL, Osto E, Scarda A, Fabris R, Montisci R, Famoso G, Tellatin S, Foletto M, Giovagnoni A, Iliceto S, Vettor R. Systemic inflammation is related to coronary microvascular dysfunction in obese patients without obstructive coronary disease. Nutr Metab Cardiovasc Dis. 2014;24:447–453.
    1. Saito M, Okayama H, Nishimura K, Ogimoto A, Ohtsuka T, Inoue K, Hiasa G, Sumimoto T, Higaki J. Possible link between large artery stiffness and coronary flow velocity reserve. Heart. 2008;94:e20.
    1. Nichols WW, Denardo SJ, Davidson JB, Huo T, Bairey Merz CN, Pepine CJ. Association of aortic stiffness and wave reflections with coronary flow reserve in women without obstructive coronary artery disease: an ancillary study from the National Heart, Lung, and Blood Institute–sponsored Women's Ischemia Syndrome Evaluation (WISE). Am Heart J. 2015;170:1243–1254.
    1. Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2008): digest version. Circ J. 2010;74:1745–1762.
    1. Lanza GA, Camici PG, Galiuto L, Niccoli G, Pizzi C, Di MA, Sestito A, Novo S, Piscione F, Tritto I, Ambrosio G, Bugiardini R, Crea F, Marzilli M. Methods to investigate coronary microvascular function in clinical practice. J Cardiovasc Med (Hagerstown). 2013;14:1–18.
    1. Matsuzawa Y, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Konishi M, Matsubara J, Sumida H, Kaikita K, Kojima S, Nagayoshi Y, Yamamuro M, Izumiya Y, Iwashita S, Matsui K, Jinnouchi H, Kimura K, Umemura S, Ogawa H. Digital assessment of endothelial function and ischemic heart disease in women. J Am Coll Cardiol. 2010;55:1688–1696.

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