Abnormal Myocardial Phosphorus-31 Nuclear Magnetic Resonance Spectroscopy in Women with Chest Pain but Normal Coronary Angiograms
Steven D. Buchthal, Ph.D., Jan A. den Hollander, Ph.D., C. Noel Bairey Merz, M.D., William J. Rogers, M.D., Carl J. Pepine, M.D., Nathaniel Reichek, M.D., Barry L. Sharaf, M.D., Steven Reis, M.D., Sheryl F. Kelsey, Ph.D., and Gerald M. Pohost, M.D.
Background After hospitalization for chest pain, women are morelikely than men to have normal coronary angiograms. In suchwomen, myocardial ischemia in the absence of clinically significantcoronary-artery obstruction has long been suspected. Most methodsfor the detection of the metabolic effects of myocardial ischemiaare highly invasive. Phosphorus-31 nuclear magnetic resonance(31P-NMR) spectroscopy is a noninvasive technique that can directlymeasure high-energy phosphates in the myocardium and identifymetabolic evidence of ischemia.
Methods We enrolled 35 women who were hospitalized for chestpain but who had no angiographically significant coronary-arteryobstructions and 12 age- and weight-matched control women withno evidence of heart disease. Myocardial high-energy phosphateswere measured with 31P-NMR spectroscopy at 1.5 tesla before,during, and after isometric handgrip exercise at a level thatwas 30 percent of the maximal voluntary grip strength. We measuredthe change in the ratio of phosphocreatine to ATP during exercise.
Results Seven (20 percent) of the 35 women with chest pain andno angiographically significant stenosis had decreases in thephosphocreatine:ATP ratio during handgrip that were more than2 SD below the mean value in the control subjects without chestpain. There were no significant differences between the twogroups with respect to hemodynamic variables at rest and duringhandgrip, risk factors for ischemic heart disease, findingson magnetic resonance imaging and radionuclide perfusion studiesof the heart, or changes in brachial flow during the infusionof acetylcholine.
Conclusions Our results provide direct evidence of an abnormalmetabolic response to handgrip exercise in at least some womenwith chest pain consistent with the occurrence of myocardialischemia but no angiographically significant coronary stenoses.
According to data from the Coronary Artery Surgery Study, morethan half of all women with chest pain who are referred forcoronary angiography do not have angiographically significantcoronary stenosis, as compared with only 17 percent of men.1Data from the Duke Data Bank2 and Kaski et al.3 indicate a similarlylow prevalence of angiographically significant coronary stenosisamong women with a syndrome of chest pain. Although noncardiaccauses can be responsible for the chest-pain syndrome, myocardialischemia in the absence of angiographically significant coronarystenoses has long been a suspected cause.4,5
One strategy for the detection of ischemia in patients withchest pain and no angiographically significant coronary stenoseshas focused on an evaluation of metabolic markers, includingmeasurements of lactate production6 and the oxygen saturationof blood from the coronary sinus.7 Both these methods are invasiveand subject to sampling errors.8 Phosphorus-31 nuclear magneticresonance (31P-NMR) spectroscopy can be used to measure themyocardial high-energy phosphates phosphocreatine and ATP andto determine the ratio of phosphocreatine to ATP. Calculationof the ratio has been useful in identifying ischemia in animals9,10and humans with coronary stenoses.11,12,13,14,15,16
We designed a multicenter study — the Women's IschemiaSyndrome Evaluation — to investigate new and innovativetechniques for the detection of ischemic heart disease in women.A specific aim of the study was to investigate the prevalenceand pathophysiology of myocardial ischemia in the absence ofangiographically significant stenoses. Accordingly, we usedthe results of 31P-NMR spectroscopy during low-level isometrichandgrip exercise as a metabolic marker for myocardial ischemiain women with chest pain and no angiographically significantstenoses.
Methods
Study Population
The population consisted of 35 women (age range, 31 to 72 years;mean [±SD], 57±10) who were admitted to the Universityof Alabama at Birmingham Medical Center with chest pain andno coronary luminal stenoses of more than 20 percent in anyepicardial coronary artery according to an evaluation by theangiographic core laboratory at Rhode Island Hospital. Thesewomen underwent magnetic resonance studies of cardiac function,magnetic resonance perfusion imaging, and radionuclide myocardialperfusion imaging in addition to coronary angiography as partof the study protocol.17 A reference population was recruitedto determine the response to stress induced by isometric handgripexercise, as measured by the phosphocreatine:ATP ratio, among12 healthy age- and weight-matched women (age range, 39 to 70years; mean, 51±8) who had no evidence of heart diseaseon the basis of exercise stress testing and risk-factor analysisaccording to the National Cholesterol Education Program guidelines.18A third group with stenosis of at least 70 percent in the leftanterior descending coronary artery was also studied and consistedof four women and seven men. These patients ranged in age from52 to 74 years (mean, 64±9). The angiograms of thesepatients were evaluated in a blinded fashion by the membersof the Department of Cardiovascular Disease at the Universityof Alabama at Birmingham. All subjects provided informed consent,and their physicians approved their participation.
31P-NMR Spectroscopy
All subjects underwent 31P-NMR spectroscopy (Gyroscan ACS, Philips,Best, the Netherlands) at 1.5 tesla in the supine position.A 10-cm surface coil for transmission and receiving was placedover the precordium and secured with a Velcro strap to minimizerespiratory artifacts. Heart rate and blood pressure were monitoredthroughout the procedure. After tuning and matching the surfacecoil, "scout" proton images were obtained in the transverseand sagittal orientations with use of a standard spin–echotechnique (echo time, 28 msec). A volume of 160 to 200 cc, includingthe anterior wall and apex of the left ventricle but excludingthe chest-wall muscle, was defined from the scout images. Appropriateadjustments were made to optimize the proton signal. We confirmedthe position of the coil by identifying on the images a smallvial containing phenylphosphonate located at the coil's center.This vial was also used to calibrate the 180-degree pulse. Thelocalization technique used was image-selected in vivo spectroscopy(ISIS). Studies of phosphate solutions showed that the signalfrom within the designated area (voxel) accounted for 90 percentof the total signal, indicating excellent localization. Thecenter frequency was set approximately 100 Hz up field fromthe phosphocreatine peak (midpoint in the spectral range). Acardiac-gated spectrum was obtained with the subject at restwith the use of adiabatic half-passage pulses. The adiabaticpulses ensure that excitation is uniform throughout the voxel.The spectral acquisition variables were as follows: repetitiontime, 3 seconds; 1024 points; sweep width, 2000 Hz; and 128averages. The time required for a single spectrum ranged from7.5 to 9 minutes, depending on the heart rate. Additional spectrawere obtained during and after isometric handgrip exercise.In some cases, the heart was far enough from the coil (7 cm)that a coronal ISIS plane (3 to 3.5 cm thick) was used insteadof a cubic voxel to increase the available signal-to-noise ratio.Location within the ISIS plane was based on the coil's sensitivityprofile, which decreases in geometric fashion as the distancefrom the coil's center increases.
Under these conditions, it is probable that lung and liver tissuewill be included in the voxel. However, lung tissue has no appreciable31P-NMR signal in vivo, and the amount of blood contained withinthe lung tissue is corrected for during data processing. Liverhas a strong 31P-NMR signal from ATP and monophosphates anddiphosphates; however, liver has no phosphocreatine. Therefore,any measurable phosphocreatine signal must come from the myocardium.Although the recorded phosphocreatine:ATP ratio of the voxelwill be lower because of the liver's contribution to the ATPsignal, the relative change in the ratio as a result of stresstesting will not be affected, since any change primarily reflectschanges in myocardial phosphocreatine.
The nuclear magnetic resonance technique that we used differedfrom that used by either Weiss et al.15 or Yabe et al.,16 whoused one-dimensional chemical shift imaging and depth-resolvedspectroscopy, respectively. All three techniques use surfacecoils whose sensitivity is subject to the weighting of the measuredsignals according to their distance from the coil. This approachleads to a greater sensitivity to spectra generated from anteriormyocardium than to spectra generated from posterior myocardium.Accordingly, the focal area in our study and the previous studieswas the anterior wall (generally, the left anterior descendingcoronary artery). The use of a surface coil to transmit theradio frequency also causes a nonuniform excitation throughthe area of interest. The use of adiabatic pulses in our studyensured that excitation was uniform; however, it still did notallow adequate sampling of the posterior wall, because of thedistance of the wall from the coil. Although we used a largervoxel than was used in the previous studies, a large portionof the volume included the ventricular chamber and tissue outsidethe myocardium, so the effective myocardial content was notgreater than in the previous studies. With the elimination ofskeletal muscle from the voxel, there was no potential auxiliarysource of phosphocreatine.
Isometric Handgrip Exercise
A hand dynamometer (Smedley, Stoelting, Wood Dale, Ill.) wasmodified for use inside the whole-body magnet. Metal componentsthat could affect the results were replaced with brass, andthe spring was replaced with Tygon silicone tubing (Norton,Akron, Ohio). Calibration of the handgrip was linear over theranges of grips obtained. To allow output to be monitored continuouslywithout compromising the radio-frequency–shielded enclosureof the scanner, we mounted the handgrip at one end of an 8-ft(2.4 m) wooden beam and connected the handgrip to a slide potentiometermounted at the opposite end. The output was monitored by computer(Biopac Systems, Santa Barbara, Calif.), with measurements obtainedthree times per second. Before entry into the whole-body magnet,the maximal voluntary grip strength of each subject was determined.During stress testing, handgrip output was maintained at 30percent of the maximal voluntary grip strength. If the outputdropped below 20 percent, the subject was asked to squeeze harderto achieve a level of 30 percent. If the heart rate and bloodpressure did not return to resting levels approximately 10 minutesafter testing, the subject was monitored for 10 additional minutes.The entire procedure took 65 to 75 minutes from the time thesubject entered the magnet.
Among the 58 subjects, only 1 (2 percent) was unable to completethe exercise regimen and 2 (3 percent) reported mild chest painduring testing that disappeared after testing was completed.None of the subjects had ST-segment changes during testing.
Statistical Analysis
Studies and data processing were conducted with the researchersunaware of the heart disease status of the subjects. Data obtainedduring 31P-NMR spectroscopy were transferred to a computer workstation(Sparc 10, Sun Microsystems, Mountain View, Calif.) for processingwith Sunspec and Fitmasters software (Philips), with peak positionsknown. The data were summed and fitted automatically after frequencyoffset and estimates of the starting phase had been entered.The fit of the summed data was used for processing individualspectra. The ratio of the areas of phosphocreatine and ATP wereadjusted for both blood volume within the left ventricular cavityand differences in T1 between phosphocreatine and ATP. We calculatedthe standard deviation of the phosphocreatine:ATP ratio usingthe Cramér-Rao lower bound,19,20 which estimates thequality of the fit on the basis of the noise of the measurement.This value ranged from 10.6 to 16.4 percent of the ratio forall the measurements obtained. The phosphocreatine:ATP ratioand hemodynamic measurements obtained during exercise were comparedwith the average of the ratios obtained at rest.
We determined the variability in the results of spectrometryby making six consecutive measurements of the resting phosphocreatine:ATPratio in a single setting in a 27-year-old man. The mean phosphocreatine:ATPratio of all six measurements was 1.63±0.19, with thestandard deviation of any individual measurement ranging from10.6 to 13.3 percent. The reproducibility of the results ofexercise stress testing was assessed in a single subject whowas tested five times over a two-week period. The changes inthe phosphocreatine:ATP ratio ranged from a decrease of 10 percentto an increase of 10 percent (mean, +0.6±11 percent).The threshold for an abnormal phosphocreatine:ATP ratio in responseto stress testing was –22.6 percent, 2 SD below the meanvalue for the reference population; lower values were consideredabnormal.
Among the women with chest pain and no coronary luminal stenosesof more than 20 percent, women with normal phosphocreatine:ATPratios during stress testing were compared with women with abnormalresponses with the use of t-tests for continuous data and Fisher'sexact test for dichotomous data.
Results
The phosphocreatine:ATP ratios in the three study groups aresummarized in Figure 1. In the reference population of 12 age-and weight-matched control women, the phosphocreatine:ATP ratiodecreased by a mean of 2.6±10.0 percent in response tostress testing, a response that is similar to changes previouslyreported in other studies.15,16 Among the patients with stenosisof the left anterior descending coronary artery of at least70 percent, the decrease in the phosphocreatine:ATP ratio wassignificantly greater (19.6± 10.7 percent, P=0.001).
Figure 1. Mean (±SD) and Individual Changes in Phosphocreatine:ATP Ratios during Handgrip Stress Testing in 35 Women with Chest Pain and Coronary-Artery Stenosis of 20 Percent or Less, 12 Age- and Weight-Matched Control Women with No Evidence of Heart Disease, and 11 Patients with Stenosis of at Least 70 Percent.
The mean decrease in the phosphocreatine:ATP ratio was 6.6±15.5 percent among the women with chest pain, 2.6±10.0 percent among the control women, and 19.6±10.7 percent among the patients with stenosis of at least 70 percent. The dotted line marks the threshold for an abnormal response (–22.6 percent), a value that was 2 SD below the mean value for the normal subjects; results below this value were considered abnormal.
The response among the 35 women with chest pain and coronary-arterystenosis of no more than 20 percent spanned the range of results.Seven women in this group (20 percent) had an abnormal responseduring stress testing; the average decrease in the phosphocreatine:ATPratio was 28.7±5.1 percent. Two other women had decreasesthat were just above the threshold. Figure 2 shows the resultsof 31P-NMR spectroscopy for 2 of the 35 women in this group.The woman whose results are shown in Figure 2A had a 27 percentdecrease in the phosphocreatine:ATP ratio in response to stresstesting, whereas the woman whose results are shown in Figure 2Bhad a decrease of 1 percent. In both examples, it is evidentthat the decrease in the ratio was mostly due to a decline inphosphocreatine, since the ATP level tended to remain stable.The phosphocreatine:ATP ratio typically returned to pretestingvalues within 10 minutes after testing and returned to pretestinglevels in all subjects within 20 minutes.
Figure 2. Results of 31P-NMR Spectroscopy in Two Women with Chest Pain and Coronary-Artery Stenosis of 20 Percent or Less.
The woman whose results are shown in Panel A had a significant decrease (27 percent) in the phosphocreatine:ATP ratio during stress testing, whereas the woman whose results are shown in Panel B did not (decrease of 1 percent). The peaks of phosphocreatine (PCr), ATP, and inorganic phosphate (Pi) plus 2,3-diphosphoglycerate (2,3-DPG) are identified in Panel A. In Panel B, there is little change in the phosphocreatine:ATP ratio from period to period and only minor spectral variations in the amount of 2,3-diphosphoglycerate. The presence of this substance reflects the amount of red cells from the ventricular chamber within the area analyzed.
We examined a number of risk factors — resting hemodynamicvariables, hemodynamic response to stress testing, ejectionfraction, thickness of the left ventricular wall, the resultsof radionuclide myocardial perfusion studies during stress testing,and response of brachial flow to stress testing — to gainfurther insight into the seven women with an abnormal decreasein the phosphocreatine:ATP ratio in response to stress testing(Table 1). There were no significant differences between thissubgroup and the subgroup with a normal decrease in the phosphocreatine:ATPratio in response to stress testing in any of the variablesother than the phosphocreatine:ATP ratio. In addition, therewas no correlation between the increase in the product of theheart rate and systolic blood pressure (rate–pressureproduct) and the change in the phosphocreatine:ATP ratio duringstress testing.
Table 1. Characteristics of Women with a Normal Response to Stress Testing and Women with an Abnormal Response.
Discussion
Our results provide direct evidence of a myocardial metabolicchange in women with chest pain and no angiographically significantcoronary stenoses. One fifth of these women had an abnormaldecrease in the myocardial phosphocreatine:ATP ratio duringmild handgrip exercise. Interestingly, the magnitude of thisdecrease was equal to or greater than that in patients withstenosis of the left anterior descending coronary artery ofat least 70 percent.
These results suggest that among women with chest pain but withoutcoronary stenoses, a subgroup has metabolic evidence of myocardialischemia during mild stress testing. The threshold we set foran abnormal response was 2 SD below the mean value for the referencepopulation. Assuming a gaussian distribution, we estimate that1 of 40 measurements (2.5 percent) should be below this threshold.Twenty percent of our patients had abnormal results. Since wemeasured the phosphocreatine:ATP ratio on a continuous scale,the threshold value can be adjusted after further refinementand verification. This may cause the threshold to shift upward,which would then shift the two patients with borderline resultsinto the subgroup with abnormal responses, increasing the percentageof abnormal responses. Ultimately, with long-term follow-up,the prognostic value of this measurement can be assessed andcompared with the value of other methods of identifying ischemia.
There are several potential physiologic and metabolic mechanismsfor an abnormal decrease in the phosphocreatine:ATP ratio inresponse to stress testing in the absence of coronary stenoses,including microvascular coronary artery disease, coronary vasospasm,and elevation of left ventricular diastolic pressure (i.e.,lusitropy). Microvascular coronary artery disease is usuallyassessed clinically by intracoronary Doppler ultrasonography,which shows an inadequate increase in flow in response to adirect-acting vasodilator such as adenosine or an endothelium-dependentvasodilator such as acetylcholine. Hasdai et al. recently reportedthat 20 subjects (10 of them women) with recurrent chest painbut no angiographically significant coronary stenoses had abnormalresponses to acetylcholine.21 One third of these subjects hada reduced response of coronary blood flow to acetylcholine onDoppler ultrasonography, findings that correlated with independentlyassessed results of radionuclide perfusion studies. Other groupshave reported similar impairments in coronary-artery responsesto acetylcholine in patients with chest pain and normal coronaryarteries, although none have directly measured coronary microvascularflow or provided metabolic evidence of myocardial ischemia inresponse to this abnormality.22,23,24
Coronary vasospasm is an uncommon response to exercise and islikely to be associated with chest pain and ST-segment elevation.Only two subjects (3 percent) in our study reported chest painduring stress testing. Lusitropy causes insufficient myocardialperfusion as a result of elevated left ventricular diastolicpressure. However, we found no significant difference in theprevalence of hypertension or the thickness of the left ventricularwall between the women with a normal decrease in the phosphocreatine:ATPratio in response to stress testing and those with an abnormaldecrease. Given the concordance between our results and thoseof others,21,22,23,24 the presence of microvascular coronaryartery disease may best explain why the phosphocreatine:ATPratio was abnormal during stress testing in women with chestpain but no angiographically significant coronary stenoses.
Myocardial 31P-NMR spectroscopy is a sensitive method of identifyingischemia and ischemic damage in a number of diseases.13,14,15Bottomley et al. were the first to demonstrate that the restingphosphocreatine:ATP ratio was decreased in patients with myocardialinfarction.13 Neubauer et al. found that the resting phosphocreatine:ATPratio correlated with the clinical severity of myocardial dysfunctionand that it increased after pharmacologic treatment.14 Weisset al. reported a significant decrease in the phosphocreatine:ATPratio during isometric handgrip exercise in patients with coronarystenoses of at least 70 percent.15 This ratio did not changesignificantly during exercise in either normal subjects or patientswith nonischemic heart disease. In addition, of five patientswith coronary stenoses of at least 70 percent and an abnormaldecrease in the phosphocreatine:ATP ratio during isometric exercise,all had normal values during exercise after undergoing revascularization.
Yabe et al.16 reported a reduction in the phosphocreatine:ATPratio during handgrip exercise among patients with ischemiabut not among those without ischemia, with the use of thalliumredistribution imaging as the standard for identifying ischemia.Thus, the body of literature on 31P-NMR spectroscopy to datestrongly supports the hypothesis that decreases in the myocardialphosphocreatine:ATP ratio with handgrip exercise (which inducesmild-to-moderate stress) provide direct metabolic evidence ofthe presence of myocardial ischemia.
The decrease in the phosphocreatine:ATP ratio during stresstesting in our patients with angiographically significant coronarystenoses (mean decrease, 17.2 percent) was not as great as thatreported by Weiss et al., who noted an average decrease of 35percent among similar patients.15 Several factors in our techniquemight minimize such decreases. We averaged the measurementsover a period of approximately eight minutes. A delay in theresponse of high-energy phosphates to stress would result inan artifactually larger phosphocreatine:ATP ratio. It is alsopossi-ble that the mild exercise test we used did not generateenough stress to induce an abnormal metabolic response. Thisexplanation is unlikely, since there was no correlation betweenthe increase in the rate–pressure product and the decreasein the phosphocreatine:ATP ratio. Thus, we may have underestimatedthe true prevalence of myocardial ischemia among women withoutangiographically significant coronary stenoses.
A major limitation of our approach was the inability to assessthe phosphocreatine:ATP ratio in regions other than the anteriorwall of the heart because of decreased sensitivity of the surfacecoil at depths of more than 10 cm. Hence, our results are relevantonly with respect to the metabolic status of the anterior wallof the heart. A second limitation was the inability to measureinorganic phosphate accurately in vivo. Measurements of inorganicphosphate can provide a means of assessing pH on the basis ofthe chemical shift of the inorganic phosphate peak relativeto that of phosphocreatine. With use of a magnetic field of1.5 tesla, inorganic phosphate cannot be reliably measured,because of the overlap of the two peaks arising from the presenceof 2,3-diphosphoglycerate in red cells. We plan to perform theseexperiments in a system with a stronger magnetic field. Theimproved spectral resolution of such a system will allow pHto be monitored and will identify the acidosis associated withischemia.
A final limitation of our study was the lack of provocativecoronary-vasospasm testing in our subjects, since primary epicardialcoronary vasoconstriction is another possible mechanism of theabnormal phosphocreatine:ATP response. We believe that thisexplanation is unlikely, since none of our patients had ST-segmentelevations typical of the presence of variant angina and previousstudies in similar populations of patients with chest pain andno coronary stenoses have shown this pathophysiologic mechanismto be infrequent.21,22,23,24
In conclusion, we found that at least 20 percent of women whowere undergoing coronary angiography to evaluate chest-painsyndromes in the absence of angiographically significant coronary-arterystenoses had evidence of altered myocardial metabolism on stresstesting combined with 31P-NMR spectroscopy, suggesting the presenceof ischemia. The concordance of our work with the findings ofothers using Doppler measurements of coronary-artery flow suggeststhat microvascular coronary artery disease is a likely mechanismfor myocardial ischemia in the absence of angiographically significantstenoses. A noninvasive nontraumatic method to identify a metabolicabnormality in this subgroup of women with chest-pain syndromesmay facilitate the development of treatment for this ubiquitousdisease.
Supported by contracts (N01-HV-68161, N01-HV-68162, N01-HV-68163,and N01-HV-68164) with the National Heart, Lung, and Blood Institute,by a General Clinical Research Center grant (MO1-RR00425) fromthe National Center for Research Resources, and by grants fromthe Gustavus and Louis Pfeiffer Research Foundation, the Women'sGuild of Cedars–Sinai Medical Center, the Ladies HospitalAid Society of Western Pennsylvania, and QMED.
Source Information
From the Center for Nuclear Magnetic Resonance Research and Development (S.D.B., J.A.H., G.M.P.) and Division of Cardiovascular Disease, Department of Medicine (W.J.R., G.M.P.), University of Alabama at Birmingham, Birmingham; the Division of Cardiology, Department of Medicine, Cedars–Sinai Research Institute, Cedars–Sinai Medical Center, Los Angeles (C.N.B.M.); the Division of Cardiology, Department of Medicine, University of Florida, Gainesville (C.J.P.); the Division of Cardiology, Department of Medicine, Allegheny University of the Health Sciences, Pittsburgh (N.R.); the Division of Cardiology, Rhode Island Hospital, Providence (B.L.S.); and the Division of Cardiology, Department of Medicine (S.R.), and the Department of Epidemiology, Graduate School of Public Health (S.F.K.), University of Pittsburgh, Pittsburgh.
Address reprint requests to Dr. Pohost at the Center for NMR R&D, UAB, 828 8th Ct. S., Birmingham, AL 35294.
References
Davis KB, Chaitman B, Ryan T, Bittner V, Kennedy JW. Comparison of 15-year survival for men and women after initial medical or surgical treatment for coronary artery disease: a CASS Registry study. J Am Coll Cardiol 1995;25:1000-1009. [Abstract]
Papanicolaou MN, Califf RM, Hlatky MA, et al. Prognostic implications of angiographically normal and insignificantly narrowed coronary arteries. Am J Cardiol 1986;58:1181-1187. [CrossRef][Medline]
Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: clinical characteristics and left ventricular function: long-term follow-up study. J Am Coll Cardiol 1995;25:807-814. [Abstract]
Likoff W, Segal BL, Kasparian H. Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engl J Med 1967;276:1063-1066.
Kemp HG, Elliott WC, Gorlin R. The anginal syndrome with normal coronary arteriography. Trans Assoc Am Physicians 1967;80:59-70. [Medline]
Greenberg MA, Grose RM, Neuburger N, Silverman R, Strain JE, Cohen MV. Impaired coronary vasodilator responsiveness as a cause of lactate production during pacing-induced ischemia in patients with angina pectoris and normal coronary arteries. J Am Coll Cardiol 1987;9:743-751. [Abstract]
Crake T, Canepa-Anson R, Shapiro L, Poole-Wilson PA. Continuous recording of coronary sinus oxygen saturation during atrial pacing in patients with coronary artery disease or with syndrome X. Br Heart J 1988;59:31-38. [Free Full Text]
Camici P, Marraccini P, Lorenzoni R, et al. Metabolic markers of stress-induced myocardial ischemia. Circulation 1991;83:Suppl III:III-8.
Schaefer S, Camacho SA, Gober J, et al. Response of myocardial metabolites to graded regional ischemia: 31P NMR spectroscopy of porcine myocardium in vivo. Circ Res 1989;64:968-976. [Free Full Text]
Schaefer S, Schwartz GG, Gober JR, et al. Relationship between myocardial metabolites and contractile abnormalities during graded regional ischemia: phosphorus-31 nuclear magnetic resonance studies of porcine myocardium in vivo. J Clin Invest 1990;85:706-713.
Nunnally RL, Bottomley PA. Assessment of pharmacological treatment of myocardial infarction by phosphorus-31 NMR with surface coils. Science 1981;311:177-180.
Flaherty JT, Weisfeldt ML, Bulkley BH, Gardner TJ, Gott VL, Jacobus WE. Mechanisms of ischemic myocardial cell damage assessed by phosphorus-31 nuclear magnetic resonance. Circulation 1982;65:561-570. [Free Full Text]
Bottomley PA, Herfkens RJ, Smith LS, Bashore TM. Altered phosphate metabolism in myocardial infarction: P-31 MR spectroscopy. Radiology 1987;165:703-707. [Free Full Text]
Neubauer S, Krahe T, Schindler R, et al. 31P Magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease: altered cardiac high-energy phosphate metabolism in heart failure. Circulation 1992;86:1810-1818. [Free Full Text]
Weiss RG, Bottomley PA, Hardy CJ, Gerstenblith G. Regional myocardial metabolism of high-energy phosphates during isometric exercise in patients with coronary artery disease. N Engl J Med 1990;323:1593-1600. [Abstract]
Yabe T, Mitsunami K, Okada M, Morikawa S, Inubushi T, Kinoshita M. Detection of myocardial ischemia by 31P magnetic resonance spectroscopy during handgrip exercise. Circulation 1994;89:1709-1716. [Free Full Text]
Merz CN, Kelsey SF, Pepine CJ, et al. The Women's Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report. J Am Coll Cardiol 1999;33:1453-1461. [Free Full Text]
Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269:3015-3023. [Free Full Text]
Van de Bos A. Parameter estimation. In: Sydenham PH, ed. Handbook of measurement science. Vol. 1. Chichester, England: John Wiley, 1982.
Cramér H. Mathematical methods of statistics. Princeton, N.J.: Princeton University Press, 1946.
Hasdai D, Gibbons RJ, Holmes DR Jr, Higano ST, Lerman A. Coronary endothelial dysfunction in humans is associated with myocardial perfusion defects. Circulation 1997;96:3390-3395. [Free Full Text]
Ouyyumi AA, Cannon RO III, Panza JA, Diodati JG, Epstein SE. Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation 1992;86:1864-1871. [Free Full Text]
Egashira K, Inou T, Hirooka Y, Yamada A, Urabe Y, Takeshita A. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med 1993;328:1659-1664. [Free Full Text]
Egashira K, Inou T, Hirooka Y, et al. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest 1993;91:29-37.
McGeechan, K., Liew, G., Macaskill, P., Irwig, L., Klein, R., Klein, B. E.K., Wang, J. J., Mitchell, P., Vingerling, J. R., deJong, P. T.V.M., Witteman, J. C.M., Breteler, M. M.B., Shaw, J., Zimmet, P., Wong, T. Y.
(2009). Meta-analysis: Retinal Vessel Caliber and Risk for Coronary Heart Disease. ANN INTERN MED
151: 404-413
[Abstract][Full Text]
Cannon, R. O. III
(2009). Microvascular angina and the continuing dilemma of chest pain with normal coronary angiograms.. J Am Coll Cardiol
54: 877-885
[Abstract][Full Text]
Cassar, A., Chareonthaitawee, P., Rihal, C. S., Prasad, A., Lennon, R. J., Lerman, L. O., Lerman, A.
(2009). Lack of Correlation Between Noninvasive Stress Tests and Invasive Coronary Vasomotor Dysfunction in Patients With Nonobstructive Coronary Artery Disease. Circ Cardiovasc Interv
2: 237-244
[Abstract][Full Text]
Hoffmann, U., Bamberg, F.
(2009). Is Computed Tomography Coronary Angiography the Most Accurate and Effective Noninvasive Imaging Tool to Evaluate Patients With Acute Chest Pain in the Emergency Department?: CT Coronary Angiography Is the Most Accurate and Effective Noninvasive Imaging Tool for Evaluating Patients Presenting With Chest Pain to the Emergency Department. Circ Cardiovasc Imaging
2: 251-263
[Full Text]
Hudsmith, L. E., Neubauer, S.
(2009). Magnetic resonance spectroscopy in myocardial disease.. J Am Coll Cardiol Img
2: 87-96
[Abstract][Full Text]
Pohost, G. M.
(2008). The history of cardiovascular magnetic resonance.. J Am Coll Cardiol Img
1: 672-678
[Full Text]
Klem, I., Greulich, S., Heitner, J. F., Kim, H., Vogelsberg, H., Kispert, E.-M., Ambati, S. R., Bruch, C., Parker, M., Judd, R. M., Kim, R. J., Sechtem, U.
(2008). Value of cardiovascular magnetic resonance stress perfusion testing for the detection of coronary artery disease in women.. J Am Coll Cardiol Img
1: 436-445
[Abstract][Full Text]
Fox, A. A.
(2008). Pro: Newly Appreciated Pathophysiology of Ischemic Heart Disease in Women Mandates Changes in Perioperative Management. Anesth. Analg.
107: 29-32
[Full Text]
Han, S. H., Bae, J. H., Holmes, D. R. Jr, Lennon, R. J., Eeckhout, E., Barsness, G. W., Rihal, C. S., Lerman, A.
(2008). Sex differences in atheroma burden and endothelial function in patients with early coronary atherosclerosis. Eur Heart J
29: 1359-1369
[Abstract][Full Text]
Bittner, V.
(2008). Angina Pectoris: Reversal of the Gender Gap. Circulation
117: 1505-1507
[Full Text]
Hemingway, H., Langenberg, C., Damant, J., Frost, C., Pyorala, K., Barrett-Connor, E.
(2008). Prevalence of Angina in Women Versus Men: A Systematic Review and Meta-Analysis of International Variations Across 31 Countries. Circulation
117: 1526-1536
[Abstract][Full Text]
Lanza, G. A., Buffon, A., Sestito, A., Natale, L., Sgueglia, G. A., Galiuto, L., Infusino, F., Mariani, L., Centola, A., Crea, F.
(2008). Relation between stress-induced myocardial perfusion defects on cardiovascular magnetic resonance and coronary microvascular dysfunction in patients with cardiac syndrome X.. J Am Coll Cardiol
51: 466-472
[Abstract][Full Text]
Pennell, D. J.
(2008). Perfusion abnormality, normal coronaries, and chest pain.. J Am Coll Cardiol
51: 473-475
[Full Text]
Wong, T. Y., Cheung, N., Islam, F. M. A., Klein, R., Criqui, M. H., Cotch, M. F., Carr, J. J., Klein, B. E. K., Sharrett, A. R.
(2008). Relation of Retinopathy to Coronary Artery Calcification: The Multi-Ethnic Study of Atherosclerosis. Am J Epidemiol
167: 51-58
[Abstract][Full Text]
Anderson, J. L., Adams, C. D., Antman, E. M., Bridges, C. R., Califf, R. M., Casey, D. E. Jr, Chavey, W. E. II, Fesmire, F. M., Hochman, J. S., Levin, T. N., Lincoff, A. M., Peterson, E. D., Theroux, P., Wenger, N. K., Wright, R. S., Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Anderson, J. L., Antman, E. M., Halperin, J. L., Hunt, S. A., Krumholz, H. M., Kushner, F. G., Lytle, B. W., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B.
(2007). ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol
50: e1-e157
[Full Text]
Vermeltfoort, I. A.C., Bondarenko, O., Raijmakers, P. G.H.M., Odekerken, D. A.M., Kuijper, A. F.M., Zwijnenburg, A., van der Vis-Melsen, M. J.E., Twisk, J. W.R., Beek, A. M., Teule, G. J.J., van Rossum, A. C.
(2007). Is subendocardial ischaemia present in patients with chest pain and normal coronary angiograms? A cardiovascular MR study. Eur Heart J
28: 1554-1558
[Abstract][Full Text]
Abbate, A., Biondi-Zoccai, G. G.L., Agostoni, P., Lipinski, M. J., Vetrovec, G. W.
(2007). Recurrent angina after coronary revascularization: a clinical challenge. Eur Heart J
28: 1057-1065
[Abstract][Full Text]
Jaumdally, R., Varma, C., Macfadyen, R. J., Lip, G. Y.H.
(2007). Coronary sinus blood sampling: an insight into local cardiac pathophysiology and treatment?. Eur Heart J
28: 929-940
[Abstract][Full Text]
Lanza, G A
(2007). Cardiac syndrome X: a critical overview and future perspectives. Heart
93: 159-166
[Abstract][Full Text]
Wong, T. Y., Kamineni, A., Klein, R., Sharrett, A. R., Klein, B. E., Siscovick, D. S., Cushman, M., Duncan, B. B.
(2006). Quantitative Retinal Venular Caliber and Risk of Cardiovascular Disease in Older Persons: The Cardiovascular Health Study. Arch Intern Med
166: 2388-2394
[Abstract][Full Text]
Hoffmann, U., Pena, A. J., Moselewski, F., Ferencik, M., Abbara, S., Cury, R. C., Chae, C. U., Nagurney, J. T.
(2006). MDCT in early triage of patients with acute chest pain.. Am. J. Roentgenol.
187: 1240-1247
[Abstract][Full Text]
Wang, J J, Liew, G, Wong, T Y, Smith, W, Klein, R, Leeder, S R, Mitchell, P
(2006). Retinal vascular calibre and the risk of coronary heart disease-related death. Heart
92: 1583-1587
[Abstract][Full Text]
Johnson, B. D., Shaw, L. J., Pepine, C. J., Reis, S. E., Kelsey, S. F., Sopko, G., Rogers, W. J., Mankad, S., Sharaf, B. L., Bittner, V., Bairey Merz, C. N.
(2006). Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the NIH-NHLBI-sponsored Women's Ischaemia Syndrome Evaluation (WISE) study. Eur Heart J
27: 1408-1415
[Abstract][Full Text]
Kaski, J C
(2006). Cardiac syndrome X in women: the role of oestrogen deficiency. Heart
92: iii5-iii9
[Abstract][Full Text]
Shaw, L. J., Bairey Merz, C. N., Pepine, C. J., Reis, S. E., Bittner, V., Kelsey, S. F., Olson, M., Johnson, B. D., Mankad, S., Sharaf, B. L., Rogers, W. J., Wessel, T. R., Arant, C. B., Pohost, G. M., Lerman, A., Quyyumi, A. A., Sopko, G., for the WISE Investigators,
(2006). Insights From the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part I: Gender Differences in Traditional and Novel Risk Factors, Symptom Evaluation, and Gender-Optimized Diagnostic Strategies. J Am Coll Cardiol
47: S4-S20
[Abstract][Full Text]
Lerman, A., Sopko, G.
(2006). Women and Cardiovascular Heart Disease: Clinical Implications From the Women's Ischemia Syndrome Evaluation (WISE) Study: Are We Smarter?. J Am Coll Cardiol
47: S59-S62
[Abstract][Full Text]
Quyyumi, A. A.
(2006). Women and Ischemic Heart Disease: Pathophysiologic Implications From the Women's Ischemia Syndrome Evaluation (WISE) Study and Future Research Steps. J Am Coll Cardiol
47: S66-S71
[Abstract][Full Text]
Madaric, J., Bartunek, J., Verhamme, K., Penicka, M., Van Schuerbeeck, E., Nellens, P., Heyndrickx, G. R., Wijns, W., Vanderheyden, M., De Bruyne, B.
(2005). Hyperdynamic Myocardial Response to Beta-Adrenergic Stimulation in Patients With Chest Pain and Normal Coronary Arteries. J Am Coll Cardiol
46: 1270-1275
[Abstract][Full Text]
Marwick, T. H.
(2005). Ischaemia and outcome with normal coronary arteries. Eur Heart J
26: 2077-2078
[Full Text]
Caus, T., Kober, F., Mouly-Bandini, A., Riberi, A., Metras, D. R., Cozzone, P. J., Bernard, M.
(2005). 31P MRS of heart grafts provides metabolic markers of early dysfunction. Eur. J. Cardiothorac. Surg.
28: 576-580
[Abstract][Full Text]
Beltrame, J. F.
(2005). Advances in understanding the mechanisms of angina pectoris in cardiac syndrome X. Eur Heart J
26: 946-948
[Full Text]
Mieres, J. H., Shaw, L. J., Arai, A., Budoff, M. J., Flamm, S. D., Hundley, W. G., Marwick, T. H., Mosca, L., Patel, A. R., Quinones, M. A., Redberg, R. F., Taubert, K. A., Taylor, A. J., Thomas, G. S., Wenger, N. K.
(2005). Role of Noninvasive Testing in the Clinical Evaluation of Women With Suspected Coronary Artery Disease: Consensus Statement From the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation
111: 682-696
[Abstract][Full Text]
Bugiardini, R., Bairey Merz, C. N.
(2005). Angina With "Normal" Coronary Arteries: A Changing Philosophy. JAMA
293: 477-484
[Abstract][Full Text]
Pennell, D. J., Sechtem, U. P., Higgins, C. B., Manning, W. J., Pohost, G. M., Rademakers, F. E., van Rossum, A. C., Shaw, L. J., Yucel, E. K.
(2004). Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report. Eur Heart J
25: 1940-1965
[Full Text]
Johnson, B. D., Shaw, L. J., Buchthal, S. D., Bairey Merz, C. N., Kim, H.-W., Scott, K. N., Doyle, M., Olson, M. B., Pepine, C. J., den Hollander, J., Sharaf, B., Rogers, W. J., Mankad, S., Forder, J. R., Kelsey, S. F., Pohost, G. M.
(2004). Prognosis in Women With Myocardial Ischemia in the Absence of Obstructive Coronary Disease: Results From the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation
109: 2993-2999
[Abstract][Full Text]
Crea, F., Lanza, G. A
(2004). Angina pectoris and normal coronary arteries: cardiac syndrome X. Heart
90: 457-463
[Full Text]
Shan, K., Constantine, G., Sivananthan, M., Flamm, S. D.
(2004). Role of Cardiac Magnetic Resonance Imaging in the Assessment of Myocardial Viability. Circulation
109: 1328-1334
[Full Text]
Bairey Merz, N., Bonow, R. O., Sopko, G., Balaban, R. S., Cannon, R. O. III, Gordon, D., Hand, M. M., Hayes, S. N., Lewis, J. F., Long, T., Manolio, T. A., Maseri, A., Nabel, E. G., Desvigne Nickens, P., Pepine, C. J., Redberg, R. F., Rossouw, J. E., Selker, H. P., Shaw, L. J., Waters, D. D., Endorsed by the American College of Cardiology Fou,
(2004). Women's Ischemic Syndrome Evaluation: Current Status and Future Research Directions: Report of the National Heart, Lung and Blood Institute Workshop*: October 2-4, 2002 : Executive Summary. Circulation
109: 805-807
[Full Text]
Pepine, C. J., Balaban, R. S., Bonow, R. O., Diamond, G. A., Johnson, B. D., Johnson, P. A., Mosca, L., Nissen, S. E., Pohost, G. M., Endorsed by the American College of Cardiology Fou,
(2004). Women's Ischemic Syndrome Evaluation: Current Status and Future Research Directions: Report of the National Heart, Lung and Blood Institute Workshop: October 2-4, 2002: Section 1: Diagnosis of Stable Ischemia and Ischemic Heart Disease. Circulation
109
: e44-e46
[Full Text]
Redberg, R. F., Cannon, R. O. III, Bairey Merz, N., Lerman, A., Reis, S. E., Sheps, D. S., Endorsed by the American College of Cardiology Fou,
(2004). Women's Ischemic Syndrome Evaluation: Current Status and Future Research Directions: Report of the National Heart, Lung and Blood Institute Workshop: October 2-4, 2002: Section 2: Stable Ischemia: Pathophysiology and Gender Differences. Circulation
109
: e47-e49
[Full Text]
Shaw, L. J., Lewis, J. F., Hlatky, M. A., Hsueh, W. A., Kelsey, S. F., Klein, R., Manolio, T. A., Sharrett, A. R., Tracy, R. P., Endorsed by the American College of Cardiology Fou,
(2004). Women's Ischemic Syndrome Evaluation: Current Status and Future Research Directions: Report of the National Heart, Lung and Blood Institute Workshop: October 2-4, 2002: Section 5: Gender-Related Risk Factors for Ischemic Heart Disease. Circulation
109
: e56-e58
[Full Text]
Maseri, A., Endorsed by the American College of Cardiology Fou,
(2004). Women's Ischemic Syndrome Evaluation: Current Status and Future Research Directions: Report of the National Heart, Lung and Blood Institute Workshop: October 2-4, 2002: Perspective: New Frontiers in Detection of Ischemic Heart Disease in Women. Circulation
109
: e62-e63
[Full Text]
Kaski, J. C.
(2004). Pathophysiology and Management of Patients With Chest Pain and Normal Coronary Arteriograms (Cardiac Syndrome X). Circulation
109: 568-572
[Full Text]
Pohost, G. M., Forder, J. R.
(2003). From the atomic nucleus to man: Nuclear magnetic resonance spectroscopy, the next horizon in diagnostic cardiology. J Am Coll Cardiol
42: 1594-1595
[Full Text]
Maguire, M. G.
(2003). Explaining Gender Differences in Coronary Heart Disease: Hunting for Clues With the Ophthalmoscope. Arch Ophthalmol
121: 1328-1329
[Full Text]
Pohost, G. M., Hung, L., Doyle, M.
(2003). Clinical Use of Cardiovascular Magnetic Resonance. Circulation
108: 647-653
[Full Text]
Cosin-Sales, J., Pizzi, C., Brown, S., Kaski, J. C.
(2003). C-reactive protein, clinical presentation, and ischemic activity in patients with chest pain and normal coronary angiograms. J Am Coll Cardiol
41: 1468-1474
[Abstract][Full Text]
Schindler, T H, Nitzsche, E, Magosaki, N, Brink, I, Mix, M, Olschewski, M, Solzbach, U, Just, H
(2003). Regional myocardial perfusion defects during exercise, as assessed by three dimensional integration of morphology and function, in relation to abnormal endothelium dependent vasoreactivity of the coronary microcirculation. Heart
89: 517-526
[Abstract][Full Text]
Huang, M.-H., Ewy, G. A., Bassan, M., Collins, A., Pennell, D. J., Panting, J. R., Collins, P., Panza, J. A.
(2002). Cardiac Syndrome X. NEJM
347: 1377-1379
[Full Text]
Lanza, G A, Crea, F
(2002). The complex link between brain and heart in cardiac syndrome X. Heart
88: 328-330
[Full Text]
Panting, J. R., Gatehouse, P. D., Yang, G.-Z., Grothues, F., Firmin, D. N., Collins, P., Pennell, D. J.
(2002). Abnormal Subendocardial Perfusion in Cardiac Syndrome X Detected by Cardiovascular Magnetic Resonance Imaging. NEJM
346: 1948-1953
[Abstract][Full Text]
Wong, T. Y., Klein, R., Sharrett, A. R., Duncan, B. B., Couper, D. J., Tielsch, J. M., Klein, B. E. K., Hubbard, L. D.
(2002). Retinal Arteriolar Narrowing and Risk of Coronary Heart Disease in Men and Women: The Atherosclerosis Risk in Communities Study. JAMA
287: 1153-1159
[Abstract][Full Text]
Schulman, S. P., Thiemann, D. R., Ouyang, P., Chandra, N. C., Schulman, D. S., Reis, S. E., Terrin, M., Forman, S., Piva de Albuquerque, C., Bahr, R. D., Townsend, S. N., Cosgriff, R., Gerstenblith, G.
(2002). Effects of acute hormone therapy on recurrent ischemia in postmenopausal women with unstable angina. J Am Coll Cardiol
39: 231-237
[Abstract][Full Text]
Antonios, T.F.T, Kaski, J.C, Hasan, K.M, Brown, S.J, Singer, D.R.J
(2001). Rarefaction of skin capillaries in patients with anginal chest pain and normal coronary arteriograms. Eur Heart J
22: 1144-1148
[Abstract]
deFilippi, C. R., Rosanio, S., Tocchi, M., Parmar, R. J., Potter, M. A., Uretsky, B. F., Runge, M. S.
(2001). Randomized comparison of a strategy of predischarge coronary angiography versus exercise testing in low-risk patients in a chest pain unit: in-hospital and long-term outcomes. J Am Coll Cardiol
37: 2042-2049
[Abstract][Full Text]
Buffon, A., Rigattieri, S., Santini, S. A., Ramazzotti, V., Crea, F., Giardina, B., Maseri, A.
(2000). Myocardial ischemia-reperfusion damage after pacing-induced tachycardia in patients with cardiac syndrome X. Am. J. Physiol. Heart Circ. Physiol.
279: H2627-H2633
[Abstract][Full Text]
Maseri, A., Buchthal, S. D., Pohost, G. M.
(2000). Chest Pain and Normal Coronary Arteries. NEJM
343: 511-512
[Full Text]
(2000). Myocardial Ischemia in Absence of Coronary Occlusion in Women. JWatch Women's Health
2000: 2-2
[Full Text]
(2000). Ischemia Common in Women with Chest Pain and Normal Angiograms. Journal Watch Cardiology
2000: 2-2
[Full Text]
Cannon, R. O., Balaban, R. S.
(2000). Chest Pain in Women with Normal Coronary Angiograms. NEJM
342: 885-887
[Full Text]
7 cm) that a coronal ISIS plane (3 to 3.5 cm thick) was used instead of a cubic voxel to increase the available signal-to-noise ratio. Location within the ISIS plane was based on the coil's sensitivity profile, which decreases in geometric fashion as the distance from the coil's center increases. 
