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Please note: This study was supported in part by a Kimura Memorial HeartFoundation Research Grant; by grants for Cardiovascular Disease (16C-6) fromthe Ministry of Health, Labor, and Welfare; by a Grant for Science FrontierPromotion Program; and by Grants-In-Aid from the Ministry of Education,Culture, Sports, Science, and Technology of Japan. The authors thank KimikoKimura for technical assistance.

REFERENCES

1. Cahill BE, Morris DK. Ischemic neuropathy. Surg Gynecol Obstet1987;165:46974.

2. Schratzberger P, Schratzberg G, Silver M, et al. Favorable effect ofVEGF gene transfer on ischemic peripheral neuropathy. Nat Med2000;6:40513.

3. Simovic D, Isner JM, Rooper AH, Pieczedk A, Weinverg DH.Improvement in chronic ischemic neuropathy after intramuscularphVEGF165 gene transfer in patients with critical limb ischemia. ArchNeurol 2001;58:7618.

4. Tateishi-Yuyama E, Matsubara H, Murohara T, et al. Therapeuticangiogenesis for patients with limb ischaemia by autologous transplan-

tation of bone-marrow cells: a pilot study and a randomized controlledtrial. Lancet 2002;360:42735.5. Saito Y, Sasaki K, Katsuda Y, et al. Effect of autologous bone-marrow

cell transplantation on ischemic ulcer in patients with Buergers disease.Circ J 2007;71:118792.

Letters to the Editor

Coronary Slow-FlowPhenomenon or Syndrome YA Microvascular AnginaAwaiting Recognition

Dr. Cannon is to be complimented on his important contributionsin the description of the elusive pathophysiology of microvascularangina. We would like to contribute to his otherwise excellentreview (1) recently published in the Journalby making mention ofanother condition that also depends on an impairment in theregulation of coronary microvascular resistances and that, there-fore, should be included among the microvascular angina syn-

dromes. This condition, known as the coronary slow-flow phe-nomenon (CSFP), is increasingly recognized as a separate clinicalentity along with the classic coronary syndrome X based on 3degrees of evidence: 1) the coronary syndrome X and the CSFPdiffer mechanistically; 2) the CSFP has typical clinical features thatdiffer strikingly from those of coronary syndrome X; and, finally, 3)its prognosis is not as benign as that traditionally described forcoronary syndrome X.

Although a number of formal definitions have been proposed,the CSFP essentially consists of a delay in the progression of thecontrast injected in the coronary vasculature during coronaryangiography. Importantly, invasive studies have demonstrated that,compatible with the delayed opacification, resting coronary arteryresistances are abnormally elevated in these patients; in strikingcontrast with classic coronary syndrome X, however, these

Effects of Treatment on Symptoms, Peripheral Blood Perfusion, and Nerve FunctionTable 1 Effects of Treatment on Symptoms, Peripheral Blood Perfusion, and Nerve Function

Healthy Subjects

(n 23)

Patients

(n 14)

TAO/ASO NA 9/5

Age (yrs) 59.3 16.6 59.2 14.2

Symptoms and Peripheral Perfusion Before After

VAS NA 3.93 3.92 0.79 1.97

Pain-free walking distance, m NA 201 110 317 197

DSA score NA 0.0 0.0 0.86 0.77

Control Limb Treated Limb

Before After Before After

ABPI NA 0.89 0.20 0.89 0.20 0.59 0.24 0.70 0.20

Nerve function

MNCV, m/s 50.4 6.94 47.3 3.0 44.8 3.0 41.1 6.5 43.9 6.2

CMAP, mV 5.3 2.8 4.9 4.3 5.2 5.2 2.3 2.7 3.6 3.5

QVT, s NM 10.5 3.2 11.1 4.0 9.2 2.7 11.5 3.5

SNCV, m/s 50.0 10.7 49.5 3.7 48.3 4.5 46.8 4.3 46.5 4.9

SNAP, V 10.2 8.9 8.4 2.1 8.6 3.1 7.6 3.8 8.7 4.4

Values are expressed as mean SD. Differences between the 2 groups were analyzed by paired or unpaired Students t test. Univariate correlations were analyzed by a Pearsons correlation. p 0.05

versus healthy group. p 0.01 versus healthy group. p 0.05 versus before treatment. p 0.01 versus before treatment.

ASO arteriosclerosis obliterans; CMAP compound muscle action potential; MNCV motor nerve conduction velocity; NA not available; NM not measured; QVT quantitative vibration threshold

time; SNAP sensory nerve action potential; SNCV sensory nerve conduction velocity; TAO thromboangiitis obliterans; VAS visual analogue scale.

239JACC Vol. 56, No. 3, 2010 Correspondence

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resistances respond normally to vasodilator stimuli such as papav-erine and adenosine and during exercise (2,3). As such, abnormal-ities in the regulation of microvascular tone occur only in restingconditions in patients with the CSFP, and while coronary syn-drome X is characterized by an impaired coronary flow reserve, theCSFP is associated with a normal, or even supranormal, one (3). Inline with this abnormality, while coronary syndrome X patientstypically experience angina under stress, the CSFP is morecommonly associated with rest angina. Further, while there isgeneral agreement that coronary syndrome X occurs more com-monly in post-menopausal women, the CSFP has been typicallyfound in young male smokers (4). Finally, and most importantly,life-threatening arrhythmias and sudden cardiac death have beendescribed in these patients (5).

A number of issues still need to be clarified with regard to thepathogenesis, clinical presentation, therapy, and outcome of theCSFP. Despite these unsolved issues, the CSFP (or coronarysyndrome Y, given the proposed role of neuropeptide Y [2]) shouldbe finally recognized the status of separate clinical entity within theframework of microvascular angina, and computation of the

Thrombolysis In Myocardial Infarction frame count should be-come a routine procedure. Further, microvascular angina shouldnot be considered a single condition with a homogeneous patho-physiology and clinical pattern. Recognizing this complexity willprobably help to explain many of the controversies well describedby Dr. Cannon.

Massimo Fineschi, MD

*Tommaso Gori, MD, PhD

*Department of CardiologyUniversity Medical CenterLangenbeckstr. 1

55131 MainzGermanyE-mail: Tommaso.gori@utoronto.ca

doi:10.1016/j.jacc.2009.09.082

REFERENCES

1. Cannon RO III. Microvascular angina and the continuing dilemma ofchest pain with normal coronary angiograms. J Am Coll Cardiol2009;54:87785.

2. Beltrame JF, Limaye SB, Wuttke RD, et al. Coronary hemodynamicand metabolic studies of the coronary slow flow phenomenon. AmHeart J 2003;146:8490.

3. Fineschi M, Bravi A, Gori T. The slow coronary flow phenomenon:evidence of preserved coronary flow reserve despite increased restingmicrovascular resistances. Int J Cardiol 2008;127:35861.

4. Beltrame JF, Limaye SB, Horowitz JD. The coronary slow flowphenomenona new coronary microvascular disorder. Cardiology2002;97:197202.

5. Saya S, Hennebry TA, Lozano P, et al. Coronary slow flow phenom-enon and risk for sudden cardiac death due to ventricular arrhythmias:a case report and review of literature. Clin Cardiol 2008;31:3525.

Reply

Drs. Fineschi and Gori propose a new syndrome of coronarymicrovascular dysfunction, manifest by slow passage of contrastmedia in coronary arteries of patients presenting with acute

chest pain. They suggest coronary syndrome Y to distinguishthis syndrome from syndrome X used by some investigators

and clinicians to identify the larger group of patients withangina-like chest pain (rest or effort provoked), ischemic-appearing electrocardiographic response to exercise stress, andnormal coronary angiograms.

Consistent with my discussion in the Journal (1), I believe thatsyndrome Y with the coronary slow-flow phenomenon has

uncertainties similar to other groups of patients with chest paindespite normal coronary angiograms, whether designated as syn-drome X, microvascular angina, or something else. Thus, is thissyndrome a primary abnormality of coronary microvascular func-tion or a result of activated platelets and vasoactive debris fromplaques in epicardial arteries not apparent on visual assessment ofcoronary angiograms? From a clinical perspective, what criteria arenecessary for diagnosis? Assessment of the flow of contrast mediafrom epicardial arteries into the myocardium is largely subjectiveand may be confounded by dilation of epicardial arteries due toadministration of nitrates before coronary angiography, thus re-ducing flow velocity at that level of the circulation. Accordingly,

what Thrombolysis In Myocardial Infarction frame count could

identify patients with this syndrome with acceptable sensitivity andspecificity? Are there characteristic electrocardiographic changes tosuggest ischemia? Are troponin levels elevated to suggest myone-crosis? Are wall motion abnormalities present on echocardiogra-phy? In this regard, intense microvascular constriction, possiblydue to neurohormonal activation accompanying psychological orother life stress, has been proposed to account for the Takotsubosyndrome of reversible apical ballooning (recently reviewed byAkashi et al. [2]), but such striking wall motion abnormalitiesdo not appear with any regularity in reports referenced byDrs. Fineschi and Gori. Can imaging studies such as cardiacmagnetic resonance imaging show evidence of endocardial hypo-perfusion if performed proximate to an episode of chest pain for

patients with recurrent symptoms? Finally, what treatments cur-rently available to clinicians are effective in managing symptomsand preventing pathophysiologic (once defined) features of thisnew syndrome?

I look forward to additional clinical research that may welllegitimize this, and other, syndromes of chest pain with normalcoronary arteries and structurally normal hearts.

*Richard O. Cannon III, MD

*National Heart, Lung, and Blood InstituteNational Institutes of Health

Translational Medicine Branch, NHLBI

Building 10-CRC, Room 5-333010 Center DriveBethesda, Maryland 20892-1454E-mail: cannonr@nih.gov

doi:10.1016/j.jacc.2009.11.100

REFERENCES

1. Cannon RO III. Microvascular angina and the continuing dilemma ofchest pain with normal coronary angiograms. J Am Coll Cardiol2010;54:87785.

2. Akashi YJ, Goldstein DS, Barbaro G, Ueyama T. Takotsubo cardio-myopathy: a new form of acute, reversible heart failure. Circulation2008;118:275462.

240 Correspondence JACC Vol. 56, No. 3, 2010

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mailto:Tommaso.gori@utoronto.camailto:cannonr@nih.govmailto:cannonr@nih.govmailto:Tommaso.gori@utoronto.ca