Myocardial bridging: what have we learned in the past and will new diagnostic modalities provide new insights?

The clinical significance of myocardial bridging has been a subject of discussion and controversy since the introduction of coronary arteriography (CAG) in the early 1960s. More recently computed tomography coronary angiography (CTCA) has made it possible to visualise the overlying muscular bands and appears to have a higher sensitivity for detecting myocardial bridging than CAG. Combining CTCA with invasive techniques such as CAG should make it possible to improve our understanding of the pathophysiology of myocardial bridging and to provide answers to hitherto unresolved questions. This paper critically reviews the outcomes of previous studies and defines remaining questions that should be answered to optimise the management of the presumably fast growing number of patients in whom a diagnosis of myocardial bridging has been made.

Rhythmic sensory stimulation improves fitness by conditioning the autonomic nervous system.

BACKGROUND: Endurance training is known to alter the functioning of the autonomic nervous system, a major goal when pursuing fitness. Here, we test the hypothesis that the training-associated rhythmic sensations alone, hence without the usual accompanying physical exercise, accomplish this effect. METHOD: We studied sixteen resting healthy male volunteers, age (mean±SD) 25.9±3.7 years. During one hour we applied, at marching pace (2 bursts per second), bipolar transcutaneous electrical sensory nerve stimulation to both feet. The stimulation intensity was controlled in such a way that discharges of sensory fibres in the tibial and fibular nerves were induced, while motor fibres were not excited. Heart rate, blood pressure, and baroreflex sensitivity were measured before and after stimulation. RESULTS: Baseline baroreflex sensitivity and systolic blood pressure were 8.7±4.5 ms·mmHg-1 and 117.5±6.4 mmHg, respectively. Directly after rhythmic sensory stimulation baroreflex sensitivity had increased to 10.0±4.1 ms·mmHg-1 (p<0.05). One day later, systolic blood pressure had lowered to 111.7±5.5 mmHg (p<0.01). CONCLUSIONS: Rhythmic sensory stimulation entails autonomic adaptations that are comparable with those of exercise. This demonstration of sensory-induced autonomic adaptations without any muscular involvement may help to design alternative, low-effort fitness programmes for specific categories of sedentary, diseased or disabled persons.

Pravastatin and endothelium dependent vasomotion after coronary angioplasty: the PREFACE trial.

OBJECTIVE: To test the hypothesis that the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor pravastatin ameliorates endothelium mediated responses of dilated coronary segments: the PREFACE (pravastatin related effects following angioplasty on coronary endothelium) trial. DESIGN: A double blind, randomised, placebo controlled, multicentre study. SETTING: Four hospitals in the Netherlands. PATIENTS: 63 non-smoking, non-hypercholesterolaemic patients scheduled for elective balloon angioplasty (pravastatin 34, placebo 29). INTERVENTIONS: The effects of three months of pravastatin treatment (40 mg daily) on endothelium dependent vasomotor function were studied. Balloon angioplasty was undertaken one month after randomisation, and coronary vasomotor function tests using acetylcholine were performed two months after balloon angioplasty. The angiograms were analysed quantitatively. MAIN OUTCOME MEASURES: The efficacy measure was the acetylcholine induced change in mean arterial diameter, determined in the dilated segment and in an angiographically normal segment of an adjacent non-manipulated coronary artery. RESULTS: Increasing acetylcholine doses produced vasoconstriction in the dilated segments (p = 0.004) but not in the normal segments. Pravastatin did not affect the vascular response to acetylcholine in either the dilated segments (p = 0.09) or the non-dilated sites. Endothelium dependent vasomotion in normal segments was correlated with that in dilated segments (r = 0.47, p < 0.001). There were fewer procedure related events in the pravastatin group than in the placebo group (p < 0.05). CONCLUSIONS: Endothelium dependent vasomotion in normal segments is correlated with that in dilated segments. A significant beneficial effect of pravastatin on endothelial function could not be shown, but in the dilated segments there was a trend towards a beneficial treatment effect in the pravastatin group.

Raman microspectroscopy of human coronary atherosclerosis: biochemical assessment of cellular and extracellular morphologic structures in situ.

BACKGROUND: We have previously shown that Raman spectroscopy can be used for chemical analysis of intact human coronary artery atherosclerotic lesions ex vivo without tissue homogenization or extraction. Here, we report the chemical analysis of individual cellular and extracellular components of atherosclerotic lesions in different stages of disease progression in situ using Raman microspectroscopy. METHODS: Thirty-five coronary artery samples were taken from 16 explanted transplant recipient hearts, and thin sections were prepared. Using a high-resolution confocal Raman microspectrometer system with an 830-nm laser light, high signal-to-noise Raman spectra were obtained from the following morphologic structures: internal and external elastic lamina, collagen fibers, fat, foam cells, smooth muscle cells, necrotic core, beta-carotene, cholesterol crystals, and calcium mineralizations. Their Raman spectra were modeled by using a linear combination of basis Raman spectra from the major biochemicals present in arterial tissue, including collagen, elastin, actin, myosin, tropomyosin, cholesterol monohydrate, cholesterol linoleate, phosphatidyl choline, triolein, calcium hydroxyapatite, calcium carbonate, and beta-carotene. RESULTS: The results show that the various morphologic structures have characteristic Raman spectra, which vary little from structure to structure and from artery to artery. The biochemical model described the spectrum of each morphologic structure quite well, indicating that the most essential biochemical components were included in the model. Furthermore, the biochemical composition of each structure, indicated by the fit contributions of the biochemical basis spectra of the morphologic structure spectrum, was very consistent. CONCLUSIONS: The Raman spectra of various morphologic structures in normal and atherosclerotic coronary artery may be used as basis spectra in a linear combination model to analyze the morphologic composition of atherosclerotic coronary artery lesions.

Diagnosis of human coronary atherosclerosis by morphology-based Raman spectroscopy.

BACKGROUND: Recent studies have shown that chemical composition and morphology, rather than anatomy (degree of stenosis), determine atherosclerotic plaque instability and predict disease progression. Current clinical diagnostic techniques provide accurate assessment of plaque anatomy, but have limited capability to assess plaque morphology in vivo. Here we describe a technique for a morphology-based diagnosis of atherosclerosis in the coronary arteries using Raman spectroscopy that can potentially be performed in vivo using optical fiber technology. METHODS: Raman tissue spectra were collected from normal and atherosclerotic coronary artery samples in different stages of disease progression (n=165) from explanted transplant recipient hearts (n=16). Raman spectra from the elastic laminae (EL), collagen fibers (CF), smooth muscle cells (SMC), adventitial adipocytes (AA) or fat cells, foam cells (FC), necrotic core (NC), cholesterol crystals (CC), beta-carotene containing crystals (beta-C), and calcium mineralizations (CM) were used as basis spectra in a linear least squares-minimization (LSM) model to calculate the contribution of these morphologic structures to the coronary artery tissue spectra. RESULTS: We developed a diagnostic algorithm that used the fit-contributions of the various morphologic structures to classify 97 coronary artery samples in an initial calibration data set as either nonatherosclerotic, calcified plaque, or noncalcified atheromatous plaque. The algorithm was subsequently tested prospectively in a second validation data set, and correctly classified 64 (94%) of 68 coronary artery samples. CONCLUSIONS: Raman spectroscopy provides information about the morphologic composition of intact human coronary artery without the need for excision and microscopic examination. In the future, it may be possible to use this technique to analyze the morphologic composition of atherosclerotic coronary artery lesions and assess plaque instability and disease progression in vivo.

Within-subject electrocardiographic differences at equal heart rates: role of the autonomic nervous system.

Various combinations of sympathetic and vagal tone can yield the same heart rate, while ventricular electrophysiology differs. To demonstrate this in humans, we studied healthy volunteers in the sitting position with horizontal legs. First, heart rate was increased by lowering the legs to 60 degrees and back. Thereafter, heart rate was increased by handgrip. In each subject, a leg-lowering angle was selected at which heart rate matched best with heart rate in the third handgrip minute. Thirteen subjects had a heart rate match better than 1%. Heart rate (control: 65.2+/-9.0 bpm) increased to 72.1+/-8.7 (leg lowering) and to 72.1+/-8.8 (handgrip) bpm. QRS azimuth, QRS duration, maximal T vector, T azimuth, T elevation, ST duration, QRS-T angle and QT interval differed significantly (P<0.05) between leg lowering and handgrip (QT interval 418+/-15 versus 435+/-21 ms). Also, septal dispersion of repolarization, assessed as the time difference between the apex and the end of the T wave in the V2 and V3 leads, differed significantly (V2: 96.7+/-19.3 versus 110.0+/-23.3 ms, P<0.01; V3: 88.7+/-19.3 versus 97.3+/-23.3 ms; P<0.01). Hence, leg lowering and handgrip cause different ventricular depolarization and repolarization. The hypertensive handgrip manoeuvre entails a longer QT interval and probably an increased septal dispersion of repolarization.

Increased risk for ischaemic events is related to combined RAS polymorphism.

OBJECTIVE: To determine whether the angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT(1)R A1166C) gene polymorphism interact to increase the risk of ischaemic events, and whether this can be explained by the progression of angiographically defined coronary atherosclerosis. DESIGN: Prospective defined substudy of the lipid lowering regression trial (REGRESS). SETTING: University hospital. PATIENTS: 885 male patients with stable coronary artery disease. MAIN OUTCOME MEASURES: Incidence of ischaemic events during a two year follow up; serial quantitative coronary arteriography (mean segment diameter and minimum obstruction diameter) at baseline and after two years. RESULTS: Patients who carried both the ACE-DD and AT(1)R-CC genotype had significantly more ischaemic events during the two year follow up than those carrying other genotype combinations (p = 0.035, Mantel-Haenszel test for linear association). There was no association between the two genotypes and mean segment diameter or minimum obstruction diameter at baseline or after two years. CONCLUSIONS: The suggestion that ACE-DD and AT(1)R-CC genotypes interact to increase the risk of ischaemic events is confirmed. However, this increased risk was not accompanied by increased progression of angiographically defined coronary atherosclerosis.

The importance of high-frequency paced breathing in spectral baroreflex sensitivity assessment.

OBJECTIVE: Computation of the low-frequency (LF) blood pressure variability (BPV) to heart rate variability (HRV) transfer-index is a common method to assess baroreflex sensitivity (BRS), tacitly assuming that all LF-HRV is caused by baroreflex feedback of LF-BPV. However, respiration may also cause HRV by mechanisms not involving the baroreflex. Application of narrow-band (controlled) high-frequency breathing would keep such non-baroreflex-mediated HRV best out of the LF band. Spontaneous breathing, because of its broad-band character, might cause extra, non-baroreflex-mediated, HRV in the LF band, while paced LF breathing would even concentrate most non-baroreflex-mediated HRV in the LF band. Our study addresses the likely resulting BRS overestimation. DESIGN: We recorded HRV and BPV in 20 healthy young subjects in the sitting position. We varied the sympathovagal balance by gradual leg-lowering from horizontal till 60 degrees . At each angle the subjects performed controlled 0.10 Hz, spontaneous, and controlled 0.25 Hz respiration. RESULTS: Resting BRS values were 15.5(7.2), 13.1 (3.7), and 11.6(6.2) ms/mmHg, respectively. Both the 15/min and the free breathing values differed significantly, P< 0.01 and P= 0.04, from the 6/min breathing value. With lowered legs, the BRS values were 8.2(3.4), 8.3(2.9), and 8.3(3.4) ms/mmHg, respectively. CONCLUSION: Controlled 6/min breathing caused significant BRS overestimation under resting conditions. For the group, spontaneous respiration yielded acceptable BRS values, but individual BRS values deviated sometimes considerably. Conversely, with gravitational load, the respiratory pattern had only minor impact on BRS. Our results demonstrate that the risk of an overestimated BRS value is realistic as long as respiration is not controlled and of high-frequency.

Pravastatin reduces restenosis two years after percutaneous transluminal coronary angioplasty (REGRESS trial).

The Regression Growth Evaluation Statin Study (REGRESS) is a placebo-controlled multicenter study designed to assess the effect of 2-year treatment with pravastatin on the progression and regression of angiographically documented coronary artery disease. One of the secondary end points was the occurrence of 2-year restenosis in the percutaneous transluminal coronary angioplasty (PTCA) block. We randomly assigned eligible patients to receive pravastatin 40 mg once daily or placebo. The end point was the percent diameter stenosis of the target lesion at 24 months, as assessed by (semi)quantitative coronary angiography. Two hundred twenty-one patients underwent scheduled PTCA, which was considered successful in 201 patients. One hundred seventy-eight patients underwent angiographic restudy (89%). The patients in the pravastatin group (n = 109) and placebo group (n = 112) were similar at baseline. Percent diameter stenosis before angioplasty was 78 +/- 14% (mean +/- SD) in the pravastatin group and 80 +/- 14% in the placebo group (p = 0.46). At follow-up, the percent diameter stenosis was 32 +/- 23% in the pravastatin group and 45 +/- 29% in the placebo group (p < 0.001). Clinical restenosis was significantly lower in the pravastatin group (7%) compared with the placebo group (29%) (p < 0.001). Risk reduction for all events was 58%. We conclude that treatment with pravastatin reduces 2-year clinical and angiographic restenosis.

Lipoprotein lipase activity is associated with severity of angina pectoris. REGRESS Study Group.

BACKGROUND: Raised triglyceride-rich lipoproteins significantly increase the risk for cardiovascular disease. Variation in the activity of the enzyme lipoprotein lipase (LPL), which is crucial in the removal of these lipoproteins, may therefore modulate this risk. METHODS AND RESULTS: Postheparin levels of LPL activity and mass were measured in a large cohort of male coronary artery disease patients participating in the Regression Growth Evaluation Statin Study (REGRESS), a lipid-lowering regression trial. In addition, the relationships between LPL activity and mass and severity of angina pectoris according to the NYHA classification and silent ischemia on 24-hour ambulatory ECG monitoring were assessed. Patients in different LPL activity quartiles and mass had different severities of angina; a total of 47% of patients in the lowest LPL quartile reported class III or IV angina. In contrast, only 29% in the highest activity quartile (P:=0.002) had severe angina. These parameters were supported by ambulatory ECG results, for which the total ischemic burden in the lowest LPL activity quartile was 36. 5+/-104.1 mm x min compared with 14.8+/-38.8 mm x min in the highest quartile of LPL activity (P:=0.001). LPL activity levels were strongly correlated with LPL mass (r=0.70, P:<0.0001). A significant association between the LPL protein mass and NYHA class (P:=0.012) was also demonstrated. CONCLUSIONS: We have demonstrated a significant relationship between LPL mass and activity and severity of ischemia as defined by angina class and ambulatory ECG. These results suggest that LPL influences risk for coronary artery disease by both catalytic and noncatalytic mechanisms.

In vivo determination of the molecular composition of artery wall by intravascular Raman spectroscopy.

Atherosclerotic plaque vulnerability is suggested to be determined by its chemical composition. However, at present there are no in vivo techniques available that can adequately type atherosclerotic plaques in terms of chemical composition. Previous in vitro experiments have shown that Raman spectroscopy can provide such information in great detail. Here we present the results of in vitro and in vivo intravascular Raman spectroscopic experiments, in which dedicated, miniaturized fiber-optic probes were used to illuminate the blood vessel wall and to collect Raman scattered light. The results make clear that an important hurdle to clinical application of Raman spectroscopy in atherosclerosis has been overcome, namely, the ability to obtain in vivo intravascular Raman spectra of high quality. Of equal importance is the finding that the in vivo intravascular Raman signal obtained from a blood vessel is a simple summation of signal contributions of the blood vessel wall and of blood. It means that detailed information about the chemical composition of a blood vessel wall can be obtained by adapting a multiple least-squares fitting method, which was developed previously for the analysis of in vitro spectra, to account for signal contributions of blood.

Imaging of an aneurysm of the sinus of Valsalva with transesophageal echocardiography, contrast angiography and MRI.

A sinus of Valsalva aneurysm is an uncommon congenital defect, which requires appropriate diagnosis with either echocardiography, magnetic resonance imaging or contrast angiography. Treatment consists of aortic valve repair. We describe a young woman with an aneurysm of the non-coronary sinus of Valsalva, an atrial septal defect and pulmonary insufficiency. The different imaging techniques and possibilities of surgical correction are described.

Gender differences in diagnosis and treatment of coronary artery disease from 1981 to 1997. No evidence for the Yentl syndrome.

AIMS: The aim of the present clinical study was to evaluate whether gender-related differences existed as regards the extent and localization of coronary artery lesions in patients with angiographically documented coronary artery disease, and whether these angiographic findings would lead to differences in further management. METHODS AND RESULTS: Over a 16-year period (1981-1997) we evaluated 1894 patients (1526 men, 368 women) with angiographically documented coronary artery disease (luminal stenosis >/=60%). For each patient the coronary angiographic results and subsequent revascularization procedures (percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery) were analysed. The study period was divided into the early angioplasty years (1981 to 1989) and the current angioplasty years (1990-1997). No gender differences in extent and localization of coronary angiographic lesions were observed. In men and women the incidence of single-vessel disease was 42% and 40%, two-vessel disease 27% and 27%, three-vessel disease 26% and 24%, and left main disease 5% and 8%, respectively (P=ns). Localization of disease in men and women was 36% and 39% for the left anterior descending coronary artery, 34% and 32% for the right coronary artery, and 27% and 26% for the left circumflex coronary artery, respectively (P=ns). There was a significant shift from multi-vessel disease towards single-vessel disease in both men and women (both P<0.001). As to subsequent management, a significant gender difference in favour of women was observed (P=0.021). Over time, the number of angioplasty procedures increased significantly from 11.6% to 23.2% for men (P<0.001), and for women from 17.6% to 28.0% (P=0.025), whereas the number of coronary artery bypass procedures decreased in men from 34.9% to 29. 5% (P=0.024) and in women from 42.6% to 30.6% (P=0.019). Referral to angioplasty (n=535) and coronary artery bypass surgery (n=616) in relation to the extent of the disease did not show any gender bias in favour of men. CONCLUSIONS: Our angiographic findings did not show significant gender differences as regards the extent and localization of coronary artery disease in patients with angiographically documented coronary artery disease. More importantly, no substantial evidence could be found for under-referral of women to subsequent therapeutic management. Therefore our study questions the presence of Yentl syndrome in the current era.

Clinical and angiographic outcome of stent implantation without predilatation using the Jostent Flex stent.

Conventional stenting requires predilatation which potentially increases vessel wall injury and cost of the procedure. In this study, the safety and efficacy of direct Jostent Flex (Jomed AB, Helsingborg, Sweden) stent placement was evaluated in 50 patients. Quantitative coronary angiography was performed at baseline, post-stent and 6 months follow-up. Clinical follow-up was done up to 9 months. In 50 patients (38 male/12 female; age 61+/-12 years) with stable (n = 42; 84%) or unstable (n = 8; 16%) angina, 53 Jostent Flex (JF) stents (diameter 3.2+/-0.2 mm) were implanted for 51 stenoses. Direct stenting was successful in 46 stenoses (90%). No stents were lost or damaged when retrieved after unsuccessful direct delivery. Eventually, all stents could be implanted at the target site. Angiographic success (<30% residual stenosis) was achieved in 49 lesions (96%). At 9 months, none of the patients had died. Target lesion revascularization was necessary in 4 (8%) patients at 6 months and in 2 (4%) other patients between 6 and 9 months. Minimal lumen diameter increased from 1.1+/-0.4 to 2.6+/-0.4 mm (p<0.001) after stent placement and 1.8+/-0.6 mm (p<0.001) at 6 months follow-up. Angiographic restenosis (> 50%) at 6 months was present in 24% of 49 treated stenoses. At 6 and 9 months, 39 (78%) and 41 (82%) of the patients were free of anginal symptoms and the ischemic event-free survival was 80% at 9 months. This study demonstrates the safety and efficacy of direct placement of the JF stent as well as favorable clinical and angiographic results up to 9 months after the procedure.

Correlated neurocardiologic and fitness changes in athletes interrupting training.

PURPOSE: We studied nine male Dutch top marathon skaters during a 1-month interruption of their training schedules after their last contest in the winter to investigate a possible decline in baroreflex sensitivity. METHODS: Before and after this period, a maximal exercise test was done, and at days 0, 4, 7, 14, and 28 neurocardiologic measurement sessions--heart rate and noninvasive baroreflex sensitivity, recumbent and tilt--were performed. RESULTS: Interruption of training resulted in a significant and relevant decrease in the maximal oxygen uptake (from 65.7 +/- 5.8 to 61.6 +/- 4.7 mL O2 x kg(-1) x min(-1); P = 0.03), most likely associated with decreased competitive possibilities. Resting heart rate modestly increased (from 54.6 +/- 7.2 to 58.8 +/- 7.5 bpm), however, not significantly. Heart rate during 60 degrees tilt increased considerably (from 70.1 +/- 6.1 to 80.1 +/- 9.1 bpm; P = 0.01), possibly due to a decrease in blood volume and an increase in cardiopulmonary baroreflex gain. Arterial baroreflex sensitivity decreased significantly in the recumbent (from 13.3 +/- 5.4 to 9.8 +/- 3.8 ms x mm Hg(-1), P = 0.04), but not in the 60 degrees tilt position (from 6.7 +/- 2.0 to 6.0 +/- 2.5 ms x mm Hg(-1)). The relative decrease in baroreflex sensitivity and maximal oxygen uptake correlated significantly (r = 0.71, P = 0.02). CONCLUSIONS: In summary, our data show that correlated detrimental changes in fitness and baroreflex sensitivity are measurable in these athletes after a month of interruption of training.

Intravascular ultrasound combined with Raman spectroscopy to localize and quantify cholesterol and calcium salts in atherosclerotic coronary arteries.

Coronary intravascular ultrasound (IVUS) can assess arterial wall architecture and localize large intravascular deposits, but it does not provide quantitative chemical information, which is essential in the evaluation of atherosclerotic lesions. Previously, it has been shown that Raman spectroscopy can be used to accurately quantify the relative weights of cholesterol, calcium salts, triglycerides, and phospholipids in homogenized arterial tissue. In the present study, we explore some benefits of combining IVUS and Raman spectroscopy to evaluate the intact arterial wall. IVUS images were collected in vitro from human coronary arterial segments in various stages of disease (n=7). The images were divided into radial segments (11 to 28 per image, 332 in total), each of which was classified visually as calcified or noncalcified tissue. The arteries were opened longitudinally, and Raman spectra were collected from locations at 0. 5-mm intervals across the arterial luminal circumference. The spectra were used to calculate the chemical composition of the arterial wall at the examined locations. Generally, locations containing large amounts of calcium salts, as determined with Raman spectroscopy, were classified as calcified with IVUS. However, small calcific deposits (<6% of weight) were not readily detected with IVUS. The amounts and location of cholesterol determined with Raman spectroscopy were correlated closely with the presence of cholesterol observed by histochemistry, but these deposits could not be located accurately by IVUS. The combination of Raman spectroscopy and IVUS applied in vitro provides detailed information about the amount and location of calcific deposits and lipid pools in atherosclerotic plaques. Future advances in optical fiber technology may allow simultaneous collection of Raman spectra and IVUS images through the same catheter in vivo.

Stentless bioprostheses have ideal haemodynamics, even in the small aortic root.

OBJECTIVE: To determine normal Doppler and 2D gradients and flow characteristics of the Freestyle stentless aortic bioprosthesis related to valve size. BACKGROUND: The Freestyle stentless aortic bioprosthesis is one of the newer aortic xenografts. Only limited data are available of the echocardiographic flow characteristics during a mid-term follow-up period of this valve. Therefore valve performance related to valve size was measured during a follow-up period of two years. METHODS: 175 consecutive patients with a Freestyle aortic bioprosthesis underwent an echocardiographic and Doppler examination according to a common protocol. Investigations were done within 4 weeks after operation, after 3 to 6 months, and after 1 and 2 years. RESULTS: With a valve size from 19 to 27 mm mean gradients decreased from 8.0 +/- 5.1 mmHg at discharge to 5.8 +/- 3.8 mmHg after 3-6 months (p < 0.001). Thereafter gradients remained stable. The performance index, the ratio of the measured effective orifice area in the patient divided by the effective orifice area measured in vitro increased from 69 +/- 20% at discharge to 79 +/- 29% after one, two and three years. Performance index was especially very high in the smaller sized valves with a performance index of 85 +/- 17% for the 21 mm valve. During follow-up mean gradients remained below 10 mmHg even in the 21 mm valve. CONCLUSION: Stentless xenografts have ideal haemodynamics, even in the small aortic root.

No gender bias in referral for coronary angiography after myocardial perfusion scintigraphy with technetium-99m tetrofosmin.

BACKGROUND: Several studies have shown that the application of diagnostic and invasive procedures varies between men and women. The purpose of this study was to assess if referral for coronary angiography after technetium-99m tetrofosmin myocardial perfusion scintigraphy in 616 patients with undiagnosed chest pain might demonstrate gender bias. METHODS AND RESULTS: The primary end point for this study was coronary angiography within 90 days of myocardial perfusion scintigraphy. Women had more normal perfusion images than men (207 [70.9%] vs 160 [50.5%], P < .05). Of 242 patients with abnormal images (157 men, 85 women), 28 men (17.7%) and 17 women (20.0%) were referred for further invasive testing (P = not significant). Referral for coronary angiography increased relative to the number of defects. Univariate analysis showed that reversible and persistent defects were the most predictive variables for referral to coronary angiography (odds ratio [OR] 5.45, 95% confidence interval [CI] 3.10-9.58, P < .001, and OR 2.67, 95% CI 1.52-4.67, P = .001, respectively). More importantly, multivariate analysis showed that reversible perfusion defects (OR 4.77, 95% CI 2.48-9.17, P < .001) and persistent perfusion defects (OR 2.14, 95% CI 1.11-4.14, P = .02) were predictive of subsequent coronary angiography. No significant association between gender and subsequent coronary angiography was found both in univariate and multivariate logistic regression analysis (OR 0.64, 95% CI 0.37-1.12, P = .12, and OR 0.70, 95% CI 0.36-1.36, P = .28, respectively). CONCLUSIONS: Our study reveals that after correction for the presence and the severity of myocardial perfusion abnormalities, men and women were referred to coronary angiography at a similar rate. Thus, based on the results of technetium-99m tetrofosmin myocardial perfusion imaging, no substantial evidence for a gender-related bias could be found in the referral for further invasive testing.