READERS’ COMMENTS

Migraine and CoronaryMicrovascular Dysfunction: WhatAbout the Insulting Factor for BothCerebral and Coronary Endothelia?

We read the report by Aslan et al1

investigating the association of migrainewith coronary microvascular dysfunc-tion using transthoracic Doppler echo-cardiography in a total of 40 migraineursand 35 age- and gender-matched healthysubjects. They have found that coronaryflow reserve (CFR) was significantlylower in the migraine group (regardlessof the aura) than the control group (1.99� 0.3 vs 2.90� 0.5, p<0.05). Also, CFRwas significantly lower in womencompared with men (2.32 � 0.6 vs 2.63� 0.6, p<0.05). Although it has not beenaimed primarily in this study, migrai-neurs revealed early diastolic dysfunc-tion compared with healthy controls.After controlling for possible confound-ing factors, migraine has emerged as theonly significant predictor of abnormalCFR (odds ratio 4.62, 95% confidenceinterval 1.06 to 20.61, p ¼ 0.04).

Migraine carries an increased riskfor cardiovascular and cerebrovasculardiseases that cannot be explained bytraditional cardiovascular risk factors.The mechanisms that link migraine tovascular diseases remain uncertain andare likely to be complex. The circulatingendothelial progenitor cell (EPC) numberis a surrogate biologic marker of vascularfunction, and diminished EPC counts areassociated with higher cardiovascularrisk.2 In their study, Lee et al2 showedthat circulating EPC numbers and func-tions are reduced in migraineurs, sug-gesting that EPCs can be an underlyinglink betweenmigraine and cardiovascularrisk. Also, Yetkin et al3 showed thatmigraineurs have decreased endothelium-dependent vasodilatation capacity com-pared with nonmigraineurs. Additionally,Rodríguez-Osorio et al4 proposed thatpatients with migraine show reducednumbers of EPCs and increased levels ofcalcitonin geneerelated peptide, nitricoxide (NOx), and vascular endothelialgrowth factor than control subjects. Nochanges were found for flow-mediateddilatation in interictal periods or duringheadache. Furthermore, EPCs decreased

Am J Cardiol 2014;113:570e5720002-9149/14/$ - see front matter � 2014 Elsevier I

with the time of evolution of migraine(r¼ �0.592, p<0.0001). These findingssuggest altered endothelial function withpossible pathophysiological mechanismsin patientswithmigraine. As a result of allthose previous studies, migraine may be alocal manifestation of systemic vascularvasomotion abnormalities.

Previous studies evidenced thatvascular endothelial function is mark-edly influenced by estrogen level andimproved by hormone replacementtherapy in postmenopausal womenthrough the enhancement of NOx pro-duction.5 In an in vitro study, Tsudaet al6 demonstrated that estrogen defi-ciency might be involved in the patho-physiology of vascular complications inwomen. In contrast, it has been shownthat endothelial function varied duringthe menstrual cycle in premenopausalwomen, suggesting that sex hormonestatus would have a crucial role in car-diovascular risk and other disease pro-cesses in premenopausal women.7,8

Therefore, we would like to knowwhether endogenous estrogen statusmight be associated with the coronarymicrovascular dysfunction assessed byCFR and migraine in young women inthe study of Aslan et al. It would beimportant to assess more precisely therelations between estrogen status andendothelial function during the men-strual cycle and their contribution to thepathogenesis of impaired CFR in youngwomen with migraine.

In conclusion, there would be acommon pathophysiological pathwayof impaired coronary and cerebralendothelial function in which EPCnumber and estrogen status may play arole.

U�gur Canpolat, MD

Osman Turak, MD

Fatma Nurcan Basar, MD

Derya TOK, MD

Dursun Aras, MD

Ankara, Turkey23 October 2013

1. Aslan G, Sade LE, Yetis B, Bozbas H, ErogluS, Pirat B, Can U, Muderrisoglu H. Flow in theleft anterior descending coronary artery in pa-tients with migraine headache. Am J Cardiol2013;112:1540e1544.

nc. All rights reserved.

2. Lee ST, Chu K, Jung KH, Kim DH, Kim EH,Choe VN, Kim JH, Im WS, Kang L, Park JE,Park HJ, Park HK, Song EC, Lee SK, Kim M,Roh JK. Decreased number and function ofendothelial progenitor cells in patients withmigraine. Neurology 2008;70:1510e1517.

3. Yetkin E, Ozisik H, Ozcan C, Aksoy Y, TurhanH. Decreased endothelium-dependent vasodi-latation in patients with migraine: a new aspectto vascular pathophysiology of migraine.Coron Artery Dis 2006;17:29e33.

4. Rodríguez-Osorio X, Sobrino T, Brea D,Martínez F, Castillo J, Leira R. Endothelialprogenitor cells: a new key for endothelialdysfunction in migraine. Neurology 2012;79:474e479.

5. Higashi Y, Sanada M, Sasaki S, Nakagawa K,Goto C, Matsuura H, Ohama K, Chayama K,Oshima T. Effect of estrogen replacementtherapy on endothelial function in peripheralresistance arteries in normotensive and hyper-tensive postmenopausal women. Hypertension2001;37:651e657.

6. Tsuda K, Kinoshita Y, Kimura K, Nishio I,Masuyama Y. Electron paramagnetic reso-nance investigation on modulatory effect of17beta-estradiol on membrane fluidity oferythrocytes in postmenopausal women. Arte-rioscler Thromb Vasc Biol 2001;21:1306e1312.

7. Williams MR, Westerman RA, Kingwell BA,Paige J, Blombery PA, Sudhir K, KomesaroffPA. J Clin Endocrinol Metab 2001;86:5389e5395.

8. Yorgun H, Tokgözo�glu L, Canpolat U, GürsesKM, Bozda�g G, Yapıcı Z, Sahiner L, Kaya EB,Kabakçı G, Oto A, Tuncer M, Aytemir K. Thecardiovascular effects of premature ovarianfailure. Int J Cardiol 2013;168:506e510.

http://dx.doi.org/10.1016/j.amjcard.2013.10.008

Atherosclerosis: Diagnose Locally,Treat Globally

Imori et al1 demonstrated that carotidartery stenosis, renal artery stenosis, andlower extremity peripheral arterial dis-ease often coexist in patients with cor-onary artery disease (CAD) and thatCAD severity is related to that of otheratherosclerotic lesions.

This study verifies the results of anearlier retrospective study investigatingthe presence of concomitant carotid ar-tery stenosis and peripheral arterialdisease in patients with versus withoutleft main (LM) CAD.2 Patients with LM(i.e., more advanced) CAD had morefrequently concomitant significant(�60%) carotid artery stenosis (31.2%vs 15.2%, respectively, p <0.0001) andlower mean ankle-brachial indexes(0.78 vs 0.87, respectively, p ¼ 0.042)

www.ajconline.org

Readers’ Comments 571

compared with patients without LMCAD.2 The conclusion reached was thatpatients with LM CAD have a greaterburden of advanced atherosclerosis inthe carotid and lower extremity arteriescompared with patients without LMCAD.2

These 2 studies support the theory thatsevere (but not moderate) atherosclerosisin 1 arterial bed (e.g., the coronary1e3 orthe carotid4,5 arteries) may predictconcomitant advanced vascular diseasein �1 additional arterial beds. Theaggressive management of all modifiablerisk factors (e.g., smoking, hyperlipid-emia, hypertension, diabetes) and theemployment of optimal medical treat-ment are essential to reduce not onlycardiac events (e.g., myocardial in-farctions) but also the complications and/or manifestations of atherosclerosis fromthe cerebrovascular (e.g., strokes) andlower extremity (e.g., amputations)arterial systems.

Kosmas I. Paraskevas, MD

Stylianos Koutsias, MD

Athanasios D. Giannoukas, MD

Larissa, Greece4 November 2013

1. Imori Y, Akasaka T, Ochiai T, Oyama K,Tobita K, Shishido K, Nomura Y, YamanakaF, Sugitatsu K, Okamura N, Mizuno S, ArimaK, Suenaga H, Murakami M, Tanaka Y, Mat-sumi J, Takahashi S, Tanaka S, Takeshita S,Saito S. Co-existence of carotid artery disease,renal artery stenosis, and lower extremity pe-ripheral arterial disease in patients with coro-nary artery disease. Am J Cardiol 2013;113:30e35.

2. Doonan AL, Karha J, Carrigan TP, Bavry AA,Begelman SM, Ellis SG, Yadav J, Bhatt DL.Presence of carotid and peripheral arterial dis-ease in patients with left main disease. Am JCardiol 2007;100:1087e1089.

3. Kawarada O, Yokoi Y, Morioka N, Nakata S,Higashiue S, Toshifumi M, Iwahashi M,Hatada A. Carotid stenosis and peripheral ar-tery disease in Japanese patients with coronaryartery disease undergoing coronary arterybypass grafting. Circ J 2003;67:1003e1006.

4. Paraskevas KI, Mikhailidis DP, Liapis CD.Internal carotid artery occlusion: associationwith atherosclerotic disease in other arterialbeds and vascular risk factors. Angiology2007;58:329e335.

5. Paraskevas KI, Mikhailidis DP, Liapis CD.Severe, but not moderate, carotid atheroscle-rosis may predict concomitant vascular diseasein other arterial beds. Stroke 2010;41:e597.http://dx.doi.org/10.1161/STROKEAHA.110.596049.

http://dx.doi.org/10.1016/j.amjcard.2013.11.002

Effect of Coronary Artery Calcium asa Subclinical AtherosclerosisMeasure on Cardiovascular Eventsor Other Causes of Death

Desai et al1 reported the effect ofcoronary artery calcium (CAC) as a sub-clinical atherosclerosis measure on car-diovascular disease (CVD) events or othercauses of death by a mean follow-upperiod of 7.1 years. They handled 6,581subjects (3,095men and 3,486women) asthe entire cohort of Multi-Ethnic Studyof Atherosclerosis (MESA), and thenumbers of participants who had CACscore of 0, 1 to 99, and�100 were 1,217,905, and 973 in men and 2,109, 838, and539 inwomen, respectively. Ahmed et al2

also analyzed the database of MESA andused morbidity and mortality as depen-dent variables with special emphasis onthe advantage of low-risk lifestyles andCAC. They selected 4 lifestyle factorssuch as weight, physical activity, smok-ing, and diet as the independent variables.In contrast, the change in CAC was usedas a dependent variable for the predictionof subclinical atherosclerosis.

I have a statistical concern on theoutcome of the study by Desai et al.1 Theauthors conducted multivariate analysesusing 2 types of statistical procedures forestimating the risk of CVD event or non-CVD mortality. About the statisticalprocedures in their Table 4, there was nodifference in the statistical outcomes ofCox regression and the modified analysisby Fine and Gray. The investigators usedage, race, systolic blood pressure, totaland high-density lipoprotein cholesterol,smoking status, and diabetes for theadjustment. In contrast, study site, in-come, medications for hypertension anddyslipidemia, and variables of healthylifestyles such as regular exercise, healthydiet, and weight maintenance were notused for the adjustment. The total numberof adjusting variables becomes 8,including CAC. As the number of cate-gory on CAC was 3, and the authorsfinally used 9 independent variables fortheir multivariate analysis.

Concato and Feinstein3 reported thatthe number of events per independentvariable in multivariate analysis shouldbe 10 or more to keep statistical power.This means that 90 events are indis-pensable for their analysis. From theTable 2 by Desai et al,1 the number ofCVD events in each CAC group was124, 303, and 628 in men, and 112, 265,

and 645 in women, respectively. Inaddition, the number of non-CVD deathsin each CAC group was 96, 204, and263 in men, and 84, 164, and 254 inwomen, respectively. Namely, the totalnumber of CVD events is satisfactory inboth men and women. However, a sub-analysis by classifying the cause of CVDevent showed the limited number of in-dependent variables for multivariateanalysis, which showed a wide range of95% confidence interval or not appli-cable in their Table 3. If the number ofindependent variables increases, moreevents are needed for their analysis.

Anyway, further study is needed byadjusting more independent variables intheir analysis. In addition, gender gapfor the risk assessment of CVD mor-bidity using CAC should be evaluatedquantitatively. I speculate from theirtables that there was a gender gap onCVD event except stroke. As the dis-tribution of CAC in men shifts higher inscore than that in women, hazard ratioof CAC on CVD events should bepresented in combination with otherhazard ratios of independent variablesto elucidate the gender gap on the pre-dictive ability for CVD events.

Tomoyuki Kawada, MD, PhD

Department of Hygiene and Public HealthNippon Medical School Tokyo, Japan

15 October 2013

1. Desai CS, NingH,Kang J, FolsomAR, Polak JF,Sibley CT, Tracy R, Lloyd-Jones DM.Competing cardiovascular outcomes associatedwith subclinical atherosclerosis (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol2013;111:1541e1546.

2. Ahmed HM, Blaha MJ, Nasir K, Jones SR,Rivera JJ, Agatston A, Blankstein R,Wong ND,Lakoski S, Budoff MJ, Burke GL, Sibley CT,Ouyang P, Blumenthal RS. Low-risk lifestyle,coronary calcium, cardiovascular events, andmortality: results from MESA. Am J Epidemiol2013;178:12e21.

3. Concato J, FeinsteinAR.MonteCarlomethods inclinical research: applications in multivariableanalysis. J Investig Med 1997;45:394e400.

http://dx.doi.org/10.1016/j.amjcard.2013.11.003

Low-Voltage QRS and AmplitudeAttenuation in Takotsubo Syndrome:Just an Intriguing Hypothesis orPotential Preangiographic Markers?

We thank John Madias for his interestin our article about differences and simi-larities in electrocardiogram (ECG) be-tween Takotsubo cardiomyopathy (TC)and acute coronary syndrome (ACS).1 He