JACC Vol. 17, No.2February 1991:499-506

EDITORIAL REVIEWS

Mechanisms of Angina Pectoris in Syndrome XATIILIO MASERI, FRCP, FACC, FILIPPO CREA, MD, FACC,JUAN CARLOS KASKI, MD, FACC, TOM CRAKE, MD, MRCP

London, England

499

Syndrome Xdefines a group of patients who present with typical,usually exertional angina pectoris and a normal coronary arterio­gram. They often have a positive exercise test, but direct signs ofischemia are detectable in only a minority of patients. Areducedcoronary vasodilative response to dipyridamole or pacing isobserved in such patients with or without a positive electrocardio­graphic exercise test. It is proposed that patients with syndrome Xhave a patchily distributed abnormal constriction of coronaryprearteriolar vessels not involved in metabolic autoregulation offlow. An increased resistance of prearteriolar vessels can explainthe reduced coronary vasodilative response observed in thesepatients, even when arterioles dilate maximally. Distal to the mostconstricted arterioles a localized compensatory increase of aden­osine concentration can cause angina even in the absence of

The term syndrome X was first used by Kemp (I) in hiseditorial comment accompanying an article by Arbogast andBourassa (2), in which these authors compared the featuresof a group of patients with angina and angiographicallynormal coronary arteries (Group X) with those of a group ofpatients with angina and coronary artery stenoses. Subse­quently, the term became a label for patients with normalcoronary angiograms who present with typical exertionalangina pectoris.

Patients with typical angina pectoris severe enough tojustify coronary arteriography, who were subsequentlyfound to have normal coronary arteries, represented 15% ofthose included in the Coronary Artery Surgery Study(CASS) Registry (3). Opinions about the cause of chest painin the presence of normal coronary arteriograms differwidely. Some authors (4) believe that an ischemic origin ofchest pain could be as low as 1%; others (5) suggest thatabnormal behavior of small coronary vessels indicative of acardiac origin of pain can be detected in >50% of thesepatients. This divergence of opinion is unlikely to be settleduntil the mechanisms by which small coronary vessel dys­function causes myocardial ischemia and angina pectoris are

From the Cardiovascular Research Unit, RPMS, Hammersmith Hospital,London, England.

Manuscript received May 30, 1990; revised manuscript received Septem­ber II, 1990, accepted September 26, 1990.

Address for reprints: Attilio Maseri, MD, Cardiovascular Research Unit,RPMS, Hammersmith Hospital, Ducane Road, London WI2 ONN, England.

©1991 by the American College of Cardiology

ischemia because adenosine is an algogenic substance. Ischemiacan develop when myocardial metabolic demand exceeds bloodsupply or when metabolic or pharmacologic arteriolar vasodila­tion causes excessive reduction of pressure at the origin of thearterioles and possibly prearteriolar collapse.

The more severe and confluent is the patchy prearteriolarconstriction, the more detectable become the signs of myocardialischemia. The proposed abnormal prearteriolar constriction couldbe caused by lack of endothelium-derived relaxing factor flow­mediated vasodilation, by abnormal nervous stimuli or by acombination of these two mechanisms. However, the causes ofabnormal coronary prearteriolar constriction are not necessarilythe same in all patients.

(J Am Coll CardioI1991;17:499-506)

better understood. In this report. we review the character­istics of these patients and propose a pathogenetic hypoth­esis that could explain this clinical syndrome and orientfuture research.

Clinical FeaturesDiagnostic criteria. In its broadest definition, the term

Syndrome X might include a spectrum of patients whopossibly have various cardiac or noncardiac causes of anginapectoris. Only some of these patients consistently developangina during exercise stress testing, some with and otherswithout diagnostic ST segment changes. In some patientsbut not in others, acute myocardial ischemia could bedemonstrated by measurements of coronary sinus lactateproduction (6,7) or oxygen saturation (8), by regional myo­cardial perfusion defects (9-13) or by regional ventricularwall motion abnormalities during exercise testing or pacing(9,14). However, on clinical grounds, patients who developdetectable myocardial ischemia cannot be distinguishedfrom those who do not. In the attempt to include under thelabel of syndrome X a more homogeneous group of patients.a positive response to exercise testing (angina and STsegment depression >1 mm) is often required as one of theinclusion criteria (8,15,16). In patients with a positive exer­cise test, Holter electrocardiographic (ECG) monitoringshows episodes of transient ST segment depression indistin­guishable from ischemic episodes observed in patients withchronic stable angina and, as in patients with coronary artery

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disease, a large proportion of these transient episodes arenot preceded by changes of heart rate or occur at heart rateslower than those observed during exercise (15).

Symptoms, a positive exercise test and episodes of tran­sient ST segment depression during Holter monitoring maypersist over a period of several years (17-20). However,even using strict inclusion criteria, recent careful studiesfailed to show myocardial lactate production during pacing(21), increases in pulmonary pressure during spontaneousepisodes of transient ST segment depression (16), abnormal­ities of left ventricular wall motion as assessed by two­dimensional echocardiography during dipyridamole testing(22) or decreases in coronary sinus blood oxygen saturationduring atrial pacing (in 8 of 10 patients) (8). Conversely, themajority of patients with syndrome X with and withoutischemic ECG changes during exercise testing seem toexhibit an abnormally small increase in coronary flow inresponse to dipyridamole or pacing (5,7,14,23), particularlyafter ergonovine administration (23). In one study (24) ofpatients with syndrome X, most without ischemic ECGchanges during exercise testing, an abnormal vasomotorresponse in the forearm was also observed. Therefore,although the adoption of stricter inclusion criteria such astransient ischemic ST segment shifts during anginal painshould considerably narrow the diagnostic field, the absenceof ECG changes during pain does not necessarily exclude acardiac origin of symptoms.

Distinguishing clinical features. The uncertainties aboutthe causes of the syndrome make the diagnosis of a cardiacor noncardiac origin of the pain difficult. Patients withsyndrome X with or without ischemic ECG changes oftenpresent some distinguishing clinical features not usuallyobserved in patients with critical epicardial coronary steno­ses or spasm. To date, these features have not receivedadequate consideration.

Even those patients who demonstrate transient ischemic­like ECG changes exhibit a substantial discrepancy betweenthe presence of anginal pain, usually severe, and signs ofleftventricular dysfunction during pain, which are usually mildor undetectable (16,22). This is in sharp contrast with thefrequent absence of pain despite the profound alterations ofleft ventricular function consistently associated with tran­sient ischemic ECG changes in patients with epicardialcoronary artery stenoses or spasm (25-27). Additionally,patients with syndrome X often report a prolonged durationof pain continuing for> 30 min after effort or emotion. In ourexperience, occasional episodes of pain induced by effort oremotion lasting>30 min were reported by 40% of 42 patientswith angina, a normal coronary arteriogram, no evidence ofepicardial coronary artery spasm and ischemic-like ECGchanges during exercise testing. The discrepancy betweenthe presence of anginal pain and the lack or scarcity ofobjectively detectable myocardial ischemia suggests thatpredominantly algogenic rather than ischemic stimuli oper­ate in this syndrome. Thus, any pathogenetic hypothesis thatattempts to explain the reduced coronary flow response to

vasodilatory stimuli and the possible development of ische­mia and angina in these patients should explain: 1) theoccurrence of angina and ischemic ST changes during effortsof variable intensity and occasionally also at rest, as well asthe occurrence of angina after dipyridamole; and 2) thepresence and long duration of anginal pain with minimal orno detectable ECG abnormalities and normal left ventricularfunction.

Pathogenetic HypothesisRole of small vessel disease. In the absence of both

atherosclerotic obstruction and demonstrable epicardial cor­onary artery spasm, the reduced coronary blood ~ow inresponse to vasodilatory stimuli and the occasional develop­ment of objective signs of ischemia are very likely caused bysmall vessel disease. The subjective report of a wide vari­ability of effort tolerance with occasional occurrence ofapparently spontaneous episodes and the objective finding ofvariable levels of heart rate at the onset of ST segmentdepression during Holter ECG monitoring (15,20) suggestthat the flow-limiting abnormality of small vessels is func­tional rather than organic. Thus, we believe that the mor­phologic abnormalities of small vessels observed in somestudies (28,29) represent an associated or secondary phe­nomenon rather than the actual cause of the disease. Epsteinand Cannon (30) proposed that "the impediment to flow maybe located in the small intramural prearteriolar vessels"before they give off subepicardial and subendocardialbranches. In their view, the localization of the flow impedi­ment in intramyocardial vessels before the branching pointof subepicardial vessels is necessary to account for dipyrida­mole-induced coronary transmural blood flow steal, whichthey assume is the cause of myocardial ischemia in theirpatients with "microvascular angina" (30).

Abnormal coronary vascular resistance. Although we doconcur with Epstein and Cannon (30) that a prearteriolaralteration is the most likely cause of abnormal coronaryvascular behavior, we propose a more general model inwhich the abnormality resides in a well identified functionalsegment of resistive vessels. In our model, the alteration caninvolve any site or the whole segment of the arterial vascularbed, with appreciable resistance to flow proximal to thesegment directly involved in the metabolic regulation ofcoronary blood flow (Fig. 1). We also propose that focal,sustained, compensatory release of adenosine distal to themost severely constricted prearterioles may cause persistentchest pain, possibly even in the absence of myocardialischemia.

Distribution of Resistance in the CoronaryVascular Bed

Functional components of coronary artery bed. The coro­nary artery bed is usually considered to be composed of two

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Conductivevessels

Prearteriolarvessels

Arteriolarvessels

Conductivevessels

Prearteriolarvessels

Arteriolarvessels

Aorticpressure

Capillarypressure

functional components: I) conductive vessels that offer anegligible resistance to blood flow, functioning as a bellowsby storing blood during systole (31) and dilating when flowincreases by a flow-dependent local release of endothelium­derived relaxing factor to reduce intimal shear stress forces(32); and 2) resistive vessels responsible for the regulation ofmyocardial perfusion. However, considering resistive ves­sels as a single functional vascular segment appears rathersimplistic. Coronary vascular resistance is distributed fromsmall epicardial coronary branches to capillaries, as indi­cated by the gradual continuous pressure decrease betweenthese two extremes (33,34). Yet, within this resistive seg­ment, vessels of different caliber may exhibit opposite re­sponses to the same vasoactive stimulus (35).

Resistive vessels and metabolic regulation of myocardialblood flow. We believe that a functional separation of thoseresistive vessels not directly involved in the metabolicregulation of myocardial blood flow from those directlyexposed to the effects of myocardial metabolites is importantto understand the principles that regulate coronary bloodflow. Although it is certain that epicardial coronary vesselsas well as the larger intramural branches are not directlyinvolved in the process of metabolic autoregulation of flow,the type and size of vessels involved in the metabolicregulation of flow cannot be defined histologically (36,37). Ifthe findings obtained in subepicardial vessels by directvisualization can be extrapolated across the whole wallthickness, metabolic regulation of flow appears to be con­fined to arterioles <100 ,urn in diameter (38). Thus, about

Aorticpressure

Capillarypressure I- ~--.....:::::='~

bl

Figure I. Schematic representation of a conduit coronary artery andprearteriolar and arteriolar vessels with patchily distributed prear­teriolar constriction in control conditions (A, upper panel) andduring arteriolar vasodilation (B, upper panel). In this functionalclassification, conduit coronary arteries do not have appreciableflow resistance, arteriolar vessels are responsible for the metabolicautoregulation of coronary blood flow and prearteriolar vessels arethose segments interposed between conductive arteriolar vesselswith appreciable coronary flow resistance that are responsible formaintaining perfusion pressure at the origin of arterioles withinoptimal levels. The vasodilatory reserve of arterioles distal toconstricted prearteriolar vessels is reduced because they are alreadydilated to preserve rest flow.

In conduit coronary arteries, the pressure remains similar toaortic pressure, but decreases progressively across prearteriolarvessels in proportion to their degree of constriction (A, lower panel).During metabolic or pharmacologic arteriolar vasodilation, thepressure drop increases only slightly distal to some prearteriolarvessels (ai' az, bz) because vasodilation related to flow-mediatedrelease of endothelium derived relaxing factor compensates nearlycompletely for the increased flow. The pressure drop increasesmarkedly across more constricted prearteriolar vessels (b l , c., cz)(B, lower panel). Steal can develop when an increase in flow throughCz causes a pressure decrease at the branching point distal to theconstricted segment c, so that the driving pressure becomes insuf­ficient to perfuse adequately the most constricted branch C1 andblood flow (as indicated by arrows) can become lower than duringrest conditions. The possibility of flow steal is greatly enhanced ifbranch Cz perfuses subepicardial layers of the ventricular wall witha greater flow reserve and if branch c I perfuses the subendocardiallayers with a smaller flow reserve. At the end of the prearteriolarvessels with the most marked increase in tone (b l ), intravascularpressure may become insufficient to maintain lumen patency, result­ing in vessel collapse.

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50% of total coronary vascular resistance would resideproximal to this site (36). In the absence of precise anatomiccriteria, we propose a functional definition of arteriolar andprearteriolar vessels.

Functional definition of arteriolar and prearteriolar ves­sels. Arteriolar vessels are those vessels responsible for thecontinuous physiologic matching of coronary blood flow tomyocardial oxygen consumption. The function of arteriolarvessels is to regulate flow to maintain the composition ofintracellular myocardial fluid within optimal limits for itscontractile function. This regulatory mechanism seems to belargely the result of the dynamic equilibrium between diffus­ible vasodilatory metabolites produced by myocytes andtheir washout by blood flow, perhaps with the contributionof tissue oxygen and carbon dioxide tension (31). Adenosineseems to be an important physiologic mediator of thisautoregulatory mechanism (39). Within each layer of themyocardium, flow through arterioles depends on their tone,extravascular resistance and, when they are maximallydilated, the perfusion pressure at their origin. In turn, themaintenance of this pressure within an optimal operationalrange depends on prearteriolar resistance.

Prearteriolar vessels are those vessels with significantresistance to flow interposed between conductive coronaryarteries and arteriolar vessels. The function of prearteriolarvessels is to maintain pressure at the origin of arteriolarvessels within an optimal operational range. This is achievedby 1) constricting when aortic pressure increases and dilatingwhen it decreases; and 2) dilating when coronary flowincreases above rest levels. The physiologic changes in toneof prearteriolar vessels when aortic pressure varies are likelyto be primarily maintained by the myogenic regulation ofsmooth muscle tone (40). Only when aortic pressure de­creases to very low levels does dilation of arterioles (38)intervene to compensate for the inevitable decrease in per­fusion pressure and maintain normal flow. The dilation ofprearteriolar vessels during metabolic autoregulation of flowis likely to be primarily related to flow-mediated local releaseof endothelial-derived resistance factor (32). Both myogenicand metabolic autoregulation can be modulated by neuraland humoral stimuli, which appear to have remarkablydifferent effects in successive segments of the arterial bed,even on the microvascular level (35).

Hemodynamic Consequences of AbnormalPrearteriolar Constriction

Even a small amount of constriction of prearteriolarvessels, or the failure to dilate when flow increases, wouldrequire a considerable compensatory arteriolar vasodilationto maintain adequate myocardial perfusion. Although ade­quately compensated by distal arteriolar vasodilation, anincrease in prearteriolar resistance would have three impor­tant interrelated consequences: 1) A reduction of coronaryflow reserve, as a fraction of the available arteriolar dilating

capacity, must already be utilized at rest. 2) A reduction inpressure at the origin of arteriolar vessels, because accord­ing to the general relation: flow = pressure gradient/resistance, an approximately linear increase in the pressuregradient is necessary to compensate for the increased prear­teriolar resistance to maintain rest flow. Therefore, thepressure gradient between the aorta and the origin of arteri­olar vessels must approximately double if resistance acrossprearteriolar vessels doubles and flow remains constant. 3) Asustained increase in interstitial adenosine concentration(which may in turn be responsible for the occurrence ofanginal pain).

Mechanisms of Impaired CoronaryBlood Flow

The only consistent finding in syndrome X seems to be animpaired coronary vasodilator response, which was ob­served by different investigators using different techniques(5,7,14,23). In contrast myocardial ischemia was convinc­ingly documented in only a minority of patients (6-14).

Prearteriolar constriction. We propose that the vascularabnormality responsible for these findings is located inprearteriolar vessels as just defined (Fig. 1). The abnormalconstriction of prearteriolar vessels is likely to be patchilydistributed and impair arteriolar blood flow more in the innerthan in the outer layers of the ventricular wall; a higherextravascular pressure is present in the inner myocardiallayers, thus requiring a higher pressure to oppose extramuralcompressive forces and cause prompt diastolic reopening ofthe vessels (31). The inner myocardial layers are also morelikely to develop ischemia because they have a highermyocardial oxygen consumption than the outer layers.

Distal to the most intensely constricted prearterioles,ischemia may develop either at rest or when myocardialoxygen consumption increases. During effort, ischemia maydevelop as a result of two factors that can operate incombination: 1) increase in myocardial oxygen consumptionnot matched by an adequate increase in coronary blood flowbecause of the reduced arteriolar vasodilatory reserve; and2) arteriolar vasodilation with consequent reduction in in­traluminal distending pressure, which may become insuffi­cient to oppose extramural pressure.

Transmural blood flow steal. In our model, as in themodel proposed by Epstein and Cannon (30), transmuralmyocardial blood flow steal can develop during metabolic orpharmacologic arteriolar dilation if a substantial fraction ofprearteriolar resistance is located proximal to the origin ofarterioles in the subepicardial layers and would be enhancedby an increase in the resistance interposed between theorigins of subepicardial and subendocardial arterioles. In ourmodel, however, steal could occur even in the same myo­cardial layer if a marked pressure decrease occurs proximalto the branching point of two branches with a markedlydifferent degree of constriction. Moreover, metabolic or

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pharmacologic arteriolar vasodilation could impair flowthrough a different mechanism, namely a reduction in lumi­nal diameter and even total occlusion in the terminal portionof the most constricted prearterioles as a result of theluminal instability created by the combination of increasedvasomotor tone and decreased distending pressure (41,42).Thus, arteriolar vasodilation could initiate a vicious cyclethat would prolong the impairment of flow and duration ofmyocardial ischemia.

Mechanisms of Anginal PainAdenosine as a mediator of anginal pain. We recently

demonstrated (43) that in patients with angina, intracoronaryinfusion of adenosine causes anginal pain similar to thatexperienced by these patients during daily life. We alsoobserved that theophylline, an adenosine antagonist, re­duces the intensity of spontaneous anginal pain. Thesefindings lend objective support to the hypothesis proposedby Sylven et al. (44) that adenosine is a mediator of anginalpain, which is also supported by the observation that appli­cation of adenosine to human skin blisters causes severepain (45). Because our results (43) showed that only adeno­sine concentrations greater than those required to producemaximal coronary vasodilation are algogenic, a constrictionthat elicits maximal compensatory dilation seems necessaryto cause an adequate algogenic stimulus.

Adenosine and anginal pain in syndrome X. The demon­stration that adenosine can be a chemical mediator of anginalpain could explain the discrepancy between the severity ofangina and the scarcity of objective ischemic signs in pa­tients with syndrome X compared with those with epicardialcoronary artery obstructions. In the latter, the resistancecreated by epicardial coronary stenoses is compensated forby a decrease in vascular resistance shared by all distalarterioles. When coronary flow reserve is exhausted, wide­spread myocardial ischemia develops in the whole regionsupplied by the stenotic vessel. Thus, major impairment ofcardiac function causes an unstable hemodynamic situationthat either regresses or evolves rapidly as a result of avicious cycle related to increased wall stiffness and diastolicpressure. Conversely, in the presence of a patchily distrib­uted and sparse prearteriolar constriction, the local concen­tration of adenosine may become sufficient to stimulatecardiac afferent nerves in the absence of impairment ofoverall cardiac function. The potential positive feedbackmechanisms triggered by arteriolar vasodilation and a de­crease in distending pressure, leading to further constrictionat the distal end of prearterioles and a further compensatoryincrease in adenosine concentration, could explain the pro­longed pain experienced by patients with syndrome X.

Chest pain in absence of ischemia: role of adenosine. It ispossible that in syndrome X, chest pain might occur in theabsence of ischemia, just as during intracoronary infusion ofadenosine. The possibility that a focal increase in adenosineconcentration distal to the most severely constricted arteri-

oles might cause pain in the absence of ischemia is suggestedby observations in open chest dogs. L'Abbate et al. (46)showed that the effects of a steady-state adenosine infusionare time-dependent, so that coronary flow values 100%greater than those produced by peak reactive hyperemia canbe attained after 30 min of adenosine infusion. It would beconceivable, therefore, that in the absence of impairedcardiac function, a sustained focal release of adenosinecould result in sufficient prearteriolar dilation to preventmyocardial ischemia.

Enhanced perception of painful stimuli. The patchy dis­tribution of markedly elevated adenosine concentrationscaused by the most constricted prearteriolar vessels mightalso contribute to making the algogenic stimulation supra­liminal, if the perception of pain depends on a spatiallyinhomogeneous stimulation of cardiac afferent polimodalreceptors (47). Finally, another possible component of thediscrepancy between the severity of pain and the minimalobjective alteration of cardiac function in patients withsyndrome X seems related to an enhanced perception ofpotentially painful stimuli (48-50).

Possible Causes of AbnormalPrearteriolar Constriction

Insufficient vasodilation or inappropriate vasoconstriction.The cause of prearteriolar coronary constriction may berelated to a local deficit of flow-mediated endothelium­derived relaxing factor production (32) so that prearteriolesdo not dilate when arterioles dilate and cause flow toincrease, resulting in a large pressure decrease at the end ofprearteriolar vessels. Alternatively, it could be related to aprimary inappropriate constriction of the smooth muscle thatcould result from either a very specific powerful neuralstimulus or a nonspecific hyperreactivity to a variety ofconstrictor stimuli (51) similar to that responsible for seg­mental epicardial coronary artery spasm (52,53). Our obser­vations that neuropeptide Y (54) and endothelin (55) cancause massive transmural myocardial ischemia in the ab­sence of detectable epicardial coronary artery constrictionprovide evidence that distal coronary vessels have thepotential to constrict to such an extent as to completelyoverpower metabolic autoregulation. Alpha-adrenergic stim­ulation was also shown (56) to cause hypoperfusion resultingin ischemia, but only in the presence of a critical coronarystenosis.

Resetting of myogenic control of prearteriolar tone. Alter­natively, the abnormality might be related to a resetting ofthe myogenic control (40) of tone in prearteriolar vessels,which, superimposed on the marked physiologic spatialmicroheterogeneity of myocardial perfusion (31), could re­sult in patchily distributed hypoperfusion. There is no pre­cise evidence for this mechanism, but impaired coronaryflow reserve has been reported (57,58) in hypertensive

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patients in the absence of myocardial hypertrophy in asso­ciation with angina and normal coronary arteries.

Segmental versus generalized distribution of prearteriolarabnormalities. It is still unknown whether the alteration ofprearteriolar vessels in syndrome X is distributed uniformlyin the ventricular walls or whether it is regional. Asegmentalabnormality corresponding to the territory of a major coro­nary artery branch would be compatible with a segmentalneural abnormality because the efferent sympathetic inner­vation of the heart has a segmental distribution that parallelsthat of major arterial branches (59). Conversely, distributionof the abnormality to the entire coronary arterial bed wouldsuggest a generalized alteration.

Clinical implications. The causes of prearteriolar coro­nary constriction need not be the same in all patients; thus,the evolution of the disease may vary despite a similarclinical presentation. However, in most cases these causesmust be stable because the disease tends to remain stable foryears. Understanding the causes of the abnormal prearteri­olar constriction is important because the beneficial effectsof traditional antianginal drugs in patients with syndrome Xare small and difficult to demonstrate in controlled trials.Beta-adrenergic blockers are much less effective in patientswith syndrome X than in those with chronic stable anginaand coronary artery disease (4,60-62), suggesting that areduction in myocardial oxygen consumption is not aneffective means of preventing or compensating for the un­derlying vasomotor abnormality. Calcium channel antago­nists and nitrates produce inconsistent responses (20), sug­gesting that at the doses currently used, drugs that reducevascular smooth muscle tone nonspecifically are ineffectivein preventing the abnormal segmental constriction of thoseprearteriolar vessels most severely involved. Clonidine andprazosin are also ineffective in improving symptoms orischemic ST segment changes (63). In contrast, the fact thataminophylline was found (64) to be effective in improvingsymptoms and ST segment ischemic changes is compatiblewith an important role of excessive myocardial adenosinerelease.

ConclusionsOn the basis of available information, it would seem

reasonable to postulate that a dynamic inappropriate con­striction of prearteriolar vessels can cause a limitation ofcoronary flow reserve, anginal pain and possibly myocardialischemia. Prearteriolar constriction need not be segmentallylocalized in intramyocardial vessels proximal to the origin ofsubepicardial arterioles and is likely to be nonuniform, withonly a minority of prearteriolar vessels very intensely con­stricted. During increased cardiac activity, focal myocardialischemia can result from the reduction in coronary flowreserve because some flow reserve is utilized during restconditions to compensate for the prearteriolar constriction.During increased myocardial blood flow, focal myocardialischemia can also result from the decrease in pressure at the

terminal end of the most intensely constricted prearteriolesbecause distending pressure may become insufficient toadequately oppose extravascular compressive forces andmaintain subendocardial myocardial perfusion and lumenstability. Because prearteriolar coronary constriction stimu­lates the local release of adenosine, a focal increase inmyocardial adenosine concentration, if intense and pro­longed, could cause anginal pain, even in the absence ofdetectable signs of myocardial ischemia since adenosineappears to be an adequate chemical stimulus for cardiacpain.

This hypothesis could explain the wide spectrum of clin­ical presentations ofpatients with syndrome X. At one endof the spectrum, the involvement of a large number ofprearteriolar vessels would explain the reduced coronaryflow reserve and the presence of myocardial ischemia ob­served in some patients. At the other, the involvement of avery limited number of prearterioles could explain the oc­currence of pain in the absence of detectable signs ofischemia and perhaps even in the absence of a detectablereduction in total coronary flow reserve. The difference inresponse to treatment and in evolution may be related todifferent underlying causes of the prearteriolar vasoconstric­tion. The evolution in some patients to dilated cardiomyop­athy (65) could be related to intense forms of small vesselspasm, similar to that observed in the Syrian hamster model(66).

The study of the mechanisms of inappropriate constric­tion of coronary prearteriolar vessels in syndrome X mayalso be relevant to the understanding of distal coronaryvessel constriction in acute (67) and chronic (68) ischemicsyndromes associated with epicardial coronary artery dis­ease.

Our hypothesis is intended to explain the clinical featuresof the syndrome and stimulate further research into themechanisms of this common clinical syndrome to developdiagnostic criteria that would allow a positive identificationof the cardiac origin of the pain and effective treatment.Meanwhile the term syndrome X should remain to remind usof our ignorance.

ReferencesI. Kemp HG. Left ventricular function in patients with the anginal syn­

drome and normal coronary arteriograms. Am J CardioI1973;32:375-6.2. Arbogast R. Bourassa MG. Myocardial function during atrial pacing in

patients with angina pectoris and normal coronary arteriograms: compar­ison with patients having significant coronary artery disease. Am JCardiol 1973:32:257-63.

3. Kemp HG. Kronmal RA. Vliestra RE. Frye RL. Seven year survival ofpatients with normal or near normal coronary arteriograms: a CASSregistry study. J Am Coli Cardiol 1986;7:479-83.

4. Hutchison SJ. Poole-Wilson PA. Henderson AH. Angina with normalcoronary arteries: a review. Quart J Med 1988;72:677-88.

5. Cannon RO III. Watson RM. Rosing DR. Epstein SE. Angina caused byreduced vasodilator reserve of the small coronary arteries. J Am ColiCardiol 1983: I: 1359-73.

6. Jackson G. Atkinson L. Armstrong P. Oram S. Angina with normal

lACC Vol. 17, No.2February 1991:499-506

MASERI ET AL.ANGINA IN SYNDROME X

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coronary arteriograms: value of coronary sinus lactate estimation indiagnosis and treatment. Br Heart J 1978;40:976-8.

7. Opherk D, Weihe E, Mall G, et al. Reduced coronary dilatory capacityand ultrastructural changes of the myocardium in patients with anginapectoris but normal coronary arteriograms. Circulation 1981 ;63:817-25.

8. Crake T, Canepa-Anson R, Shapiro LM, Poole-Wilson PA. Continuousrecording of coronary sinus saturation during atrial pacing in patients withand without coronary artery disease or with syndrome X. Br Heart J1987;57:67-72.

9. Legrand V, Hodgson JM, Bates ER, et al. Abnormal coronary flowreserve and abnormal radionuclide exercise test results in patients withnormal coronary angiograms. J Am Coil CardioI1985;6:1245-53.

10. Korhola 0, Valle M, Frick MH, Wiljasolo M, Riihimaki E. Regionalmyocardial perfusion abnormalities on xenon-133 imaging in patients withangina pectoris and normal coronary arteries. Am J Cardiol 1977;39:355-9.

11. Berger BC, Abramowitz R, Park CH, et al. Abnormal thallium-201 scansin patients with chest pain and angiographically normal coronary arteries.Am J Cardiol 1983;52:365-70.

12. Dunn RF, Wolft L, Wagner S, Botvinick EH. The inconsistent pattern ofthallium defects: a clue to the false positive scintigram. Am J Cardiol1981 ;48:224-32.

13. Green LH, Cohn PF, Holman BL, Adams DF, Markis JE. Regionalmyocardial blood flow in patients with chest pain syndromes and normalcoronary arteriograms. Br Heart J 1978;40:242-9.

14. Cannon RO III, Bonow RO, Bacharach SL, et al. Left ventriculardysfunction in patients with angina pectoris, normal epicardial coronaryarteries and abnormal vasodilator reserve. Circulation 1985;71 :218-26.

15. Kaski JC, Crea F, Nihoyannopoulos P, Hackett D, Maseri A. Transientmyocardial ischemia during daily life in patients with syndrome X. Am JCardioI1986;58:1242-7.

16. Levy RD, Shapiro LM, Wright C, Mockus L, Fox KM. Diurnal variationin left ventricular function: a study of patients with myocardial ischaemia,syndrome X, and of normal controls. Br Heart J 1987;57: 148-53.

17. Kemp HG, Vokonas PS, Cohn PF, Gorlin R. The anginal syndromeassociated with normal coronary arteriograms: report of a six yearexperience. Am J Med 1973;54:735-42.

18. Bemiller CR, Pepine FJ, Rogers AA. Long-term observations in patientswith angina and normal coronary arteriograms. Circulation 1973;47:36­43.

19. Isner JM, Salem DN, Banas JS, Levine HJ. Long-term clinical course ofpatients with normal or near normal coronary arteriograms. Am Heart J1981 ;102:645-53.

20. Pupita G, Kaski JC, Galassi A, Vejar M, Crea F, Maseri A. Long-termvariability ofangina pectoris and electrocardiographic signs of ischemia insyndrome X. Am J CardioI1989;64: 139-43.

21. Camici P, Marraccini P, Lorenzoni R, Ferrannini E, L'Abbate A, MarzilliM. Myocardial metabolism in syndrome X (abstr). Eur Heart J 1989;10:51.

22. Picano E, Lattanzi F, Masini M, Distante A, L'Abbate A. Usefulness ofa high-dose dipyridamole-echocardiography test for diagnosis of syn­drome X. Am J Cardiol 1987;60;508-12.

23. Cannon RO, Schenke WH, Leon MB, Rosing DR, Urqhart J, Epstein SE.Limited coronary flow reserve after dipyridamole in patients with er­gonovine-induced coronary vasoconstriction. Circulation 1987;75: 163-74.

24. Sax FL, Cannon RO III, Hanson C, Epstein SE. Impaired forearmvasodilator reserve in patients with microvascular angina: evidence of ageneralized disorder ofa vascular function? N Engl J Med 1987;317: 1366­70.

25. Cohn PF, Brown EJ Jr., Wynn J, Holman BL, Atkins HL. Global andregional left ventricular ejection fraction abnormalities during exercise inpatients with silent myocardial ischemia. J Am Coil CardioI1983;1:931-3.

26. Chierchia S, Lazzari M, Freedman B, Brunelli C, Maseri A. Impairmentof myocardial perfusion and function during painless myocardial ische­mia. J Am Coil Cardiol 1983;1:924-30.

27. Davies GJ, Bencivelli W, Fragasso G, et al. Sequence and magnitude ofventricular volume changes in painful and painless myocardial ischemia.Circulation 1988;78:310-9.

28. Mosseri M, Yarom R, Gotsman MS, Hasin Y. Histologic evidence forsmall-vessel coronary artery disease in patients with angina pectoris andpatent large coronary arteries. Circulation 1986;74:964-72.

29. van Hoeven KH, Factor SM. Endomyocardial biopsy diagnosis of smallvessel disease: a clinicopathologic study. Int J CardioI199O;26:103-10.

30. Epstein SE, Cannon RO III. Site of increased resistance to coronary flowin patients with angina pectoris and normal epicardial coronary arteries.J Am Coil Cardiol 1986;8:459-61.

31. Hoffman HE, Spaan JAE. Pressure-flow relations in coronary circulation.Physiol Rev 1990;70:331-90.

32. Bassenge E, Busse R. Endothelial modulation of coronary tone. ProgCardiovasc Dis 1988;30:349-80.

33. Klassen GA, Armour JA, Garner JB. Coronary circulatory pressuregradients. Can J Physiol PharmacoI1987;65:520-31.

34. Chilian WM, Eastham CL, Lopez AL, Marcus ML. Microvasculardistribution of coronary vascular resistance in beating left ventricle. AmJ PhysioI1986;251:H779-88.

35. Marcus ML, Chilian WM, Kanatsuka H, Dellsperger KC, Eastham CL,Lamping KG. Understanding the coronary circulation through studies atthe microvascular level. Circulation 1990;82: 1-7.

36. Schaper W, Schaper J. The coronary microcirculation. Am J Cardiol1977;40: 1008-12.

37. Shierf L, Ben-Shaul Y, Lieberman Y, Neufeld HN. The human coronarymicrocirculation: an electron microscopic study. Am J Cardiol 1977;39:599-607.

38. Kanatsuka H, Lamping KG, Eastham CL, Dellsperger KC, Marcus ML.Comparison of the effects of increased myocardial oxygen consumptionand adenosine on the coronary microvascular resistance. Circ Res 1989;65: 1296-305.

39. Rubio R, Berne RM. Release ofadenosine by the normal myocardium andits relationship to the regulation of coronary resistance. Circ Res 1969;25:407-19.

40. Johnson pe. The myogenic response. In: Handbook of Physiology. TheCardiovascular System: Vascular Smooth Muscle. Volume 2. Bethesda,Md: American Physiology Society, 1980:409-42.

41. Burton Ae. Properties of smooth muscle and regulation of circulation.Physiol Rev 1964;42: 1-6.

42. Santamore WP, Kent RL, Carey RA, Bove AA. Synergistic effects ofpressure, distal resistance and vasoconstriction of stenosis. Am J Physiol1982;243:H236-42.

43. Crea F, Pupita G, Galassi AR, et al. Role of adenosine in pathogenesis ofanginal pain. Circulation 1990;81:164-72.

44. Sylven C, Beermann B, Jonzon B, Brandt R. Angina pectoris-like painprovoked by intravenous adenosine. Br Med J 1986;293:227-30.

45. Bleehen T, Keele CA. Observations on the algogenic actions of adenosinecompounds on the human blister base preparation. Pain 1977;3:367-72.

46. L'Abbate A, Camici P, Trivella MG, et al. Time dependent response ofcoronary flow to prolonged adenosine infusion: doubling of peak reactivehyperaemic flow. Cardiovasc Res 1981;15:282-6.

47. Malliani A. Cardiovascular sympathetic afferent fibres. Rev PhysiolBiochem Pharmacol 1982;94:11-74.

48. Turiel M. Galassi AR, Glazier JJ, Kaski JC, Maseri A. Pain threshold andtolerance in women with syndrome X and women with stable anginapectoris. Am J Cardiol 1987;60:503-8.

49. Shapiro LM, Crake T, Poole-Wilson PA. Is altered cardiac sensationresponsible for chest pain in patients with normal coronary arteries?Clinical observation during cardiac catheterisation. Br Med J 1988;296:170-1.

50. Cannon RO, Quyyumi A, Schenke WH, et al. Abnormal cardiac sensi­tivity in patients with chest pain and normal coronary arteries. J Am CoilCardiol 1990: 16: 1359-66.

51. Maseri A, Davies GJ, Hackett D, Kaski Je. Coronary artery spasm andcoronary vasoconstriction: the case for a distinction. Circulation 1990;81:1983-91.

52. Kaski JC, Crea F, Meran D, et al. Local coronary supersensitivity todiverse vasoconstrictive stimuli in patients with variant angina. Circula­tion 1986;74:1255-65.

53. Kaski Je, Maseri A, Vejar M, Crea F, Hackett D. Spontaneous coronaryartery spasm in variant angina is caused by a local hyperreactivity to ageneralized constrictor stimulus. J Am Coil CardioI1989:i4:1456-63.

54. Clarke JG, Davies GJ, Kerwin R, et al. Coronary artery infusion ofneuropeptide Y in patients with angina pectoris. Lancet 1987:i:1057-9.

506 MASERI ET AL.ANGINA IN SYNDROME X

JACC Vol. 17, No.2February 1991 :499-506

55. Larkin SW, Clarke JG, Keogh BE, et al. Intracoronary endothelininduces myocardial ischemia by small vessel constriction in the dog. AmJ Cardiol 1989:64:956-8.

56. Heusch G, Deussen A. The effects of cardiac sympathetic nerve stimu­lation on perfusion of stenotic coronary arteries in the dog. Circ Res1983;53:8-15.

57. Opherk D. Mall G, Zebe HJ. et al. Reduction of coronary reserve: amechanism for angina pectoris in patients with arterial hypertension andnormal coronary arteries. Circulation 1984:69: 1-7.

58. Picano E, Lucarini AR. Lattanzi F. et aI. Dipyridamole-echocardiographytest in essential hypertensives with chest pain. Hypertension 1988: 12:238-43.

59. Randall WC. Armour JA. Regional vagosympathetic control of the heart.Am J Physiol 1974:227:444-52.

60. Ferrini 0, Bugiardini R. Galvani M. et al. Effetti opposti del propranololoe del diltiazem sulla soglia d'angina durante test da sforzo in pazienti consindrome X. G Ital CardioI1986:16:224-31.

61. Romeo F, Gaspardone A. Ciavolella M. Gioffre P, Reale A. Verapamilversus acebutolol for syndrome X. Am J Cardiol 1988:62:312-3.

62. Cannon RO. Watson RM. Rosing DR, Epstein SE. Efficacy of calcium

channel blocker therapy for angina pectoris resulting from small vesselcoronary artery disease and abnormal vasodilator reserve. Am J Cardiol1985:56:242-6.

63. Galassi A, Kaski Jc, Pupita G. Vejar M. Crea F, Maseri A. Lack ofevidence for alpha-adrenergenic receptor-mediated mechanisms in thegenesis of ischemia in syndrome X. Am J Cardiol 1989:64:264-9.

64. Emdin M, Picano E. Lattanzi F. L'Abbate A. Improved exercise capacitywith acute aminophylline administration in patients with syndrome X.J Am Coli CardioI1989:14:1450-3.

65. Kubler W. Opherk D. Tillmanns H. Syndrome X: diagnostic criteria andlong term prognosis. Can J Cardiol 1986:2(suppl A):219A-20A.

66. Sonnenblick EH. Fein F. Capasso JM. Factor SM. Microvascular spasmas a cause of cardiomyopathies and the calcium-blocking agent verapamilas potential primary therapy. Am J CardioI1985;55:179B-84B.

67. Wilson RF. Lawson DO. Lesser JR. White C. Interim microvascularconstriction after angioplasty of the acute thrombotic coronary occlusion.Lancet 1989:1:807-11.

68. Pupita G, Maseri A. Kaski Jc, et al. Myocardial ischemia caused by distalcoronary-artery constriction in stable angina pectoris. N Engl J Med1990:323:514-20.