History of anxiety disorders is associated with a decreased likelihood of angiographic coronary artery disease in women with chest pain: the WISE study.

OBJECTIVES: We sought to evaluate the ability of psychiatric anxiety-disorder history to discriminate between women with and without angiographic coronary artery disease (CAD) in a population with chest pain. BACKGROUND: A total of 435 women with chest pain underwent a diagnostic battery including coronary angiography in order to improve testing guidelines for women with suspected CAD. METHODS: Women referred for coronary angiography completed questionnaires assessing prior treatment history for anxiety disorder and current anxiety-related symptoms. Analyses controlled for standard CAD risk factors. RESULTS: Forty-four women (10%) reported receiving prior treatment for an anxiety disorder. This group acknowledged significantly higher levels of autonomic symptoms (e.g., headaches, muscle tension [F = 25.0, p < 0.0011 and higher behavioral avoidance scores (e.g., avoidance of open places or traveling alone by bus [F = 4.2, p < 0.05]) at baseline testing compared with women without prior anxiety problems. Women with an anxiety-disorder history did not differ from those without such a history with respect to the presence of inducible ischemia or use of nitroglycerin, although they were younger and more likely to describe both "tight" and "sharp" chest pain symptoms and to experience back pain and episodes of nocturnal chest pain. Logistic regression results indicated that the positive-anxiety-history group was more likely to be free of underlying significant angiographic CAD (odds ratio = 2.74, 95% confidence interval 1.15 to 6.5, p = 0.03). CONCLUSIONS: Among women with chest pain symptoms, a history of anxiety disorders is associated with a lower probability of significant angiographic CAD. Knowledge of anxiety disorder history may assist in the clinical evaluation of women with chest pain.

Diagnostic, prognostic, and cost assessment of coronary artery disease in women.

Women with obstructive coronary disease appear to be more challenging diagnostically and suffer a more adverse prognosis than men. More than one half of women with symptoms of ischemic heart disease have no obstructive coronary artery disease at coronary angiography, yet these women frequently have persistent symptom-related disability and consume large amounts of healthcare resources. Prior evidence has been limited regarding effective diagnostic strategies for the assessment of symptomatic women. The current report synthesizes existing evidence on diagnostic testing in women, including research from the ongoing National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. In addition to recent published evidence (drawn from much larger cohorts of women) that stress echocardiography and nuclear imaging are similar in their ability to risk-stratify women, the WISE study is exploring new pathophysiological mechanisms of microvascular dysfunction in women. An unfolding body of evidence suggests that as tests become more diagnostically and prognostically accurate, the process will become more cost efficient. The results from a growing number of large observational series and National Institutes of Health-sponsored studies are expected to be the foundation for cost-effective diagnostic and prognostic strategies for the approximately 5 million women who undergo evaluation for coronary disease annually.

Age-associated changes in regional aortic pulse wave velocity.

OBJECTIVES: This study was designed to determine noninvasively the age-associated changes in regional mechanical properties in normals using phase-contrast magnetic resonance imaging (PCMRI). BACKGROUND: It has been well documented that there is a progressive increase in aortic pulse wave velocity (PWV) with age. Previously, PWV has been measured at a single aortic location, or has compared arterial waves between carotid and femoral points to determine PWV. METHODS: Applanation tonometry (TONO) and in-plane PCMR was performed in 24 volunteers (12 men) ranging in age from 21 to 72 years old. The PCMRI PWV was measured in three aortic segments. As validation, TONO was performed to determine PWV between the carotid and femoral artery. RESULTS: When PCMRI PWV was averaged over the three locations, it was not different from TONO (7.9 +/- 2.3 vs. 7.6 +/- 2.4 m/s, respectively). When the volunteers were divided into groups of < 55 and > or =55 years old, the younger group showed similar PWV at each aortic location. However, the older group displayed significantly increased PWV in the region spanning the ascending and proximal descending aorta compared with the mid-thoracic or abdominal segments (10.6 +/- 2.5 m/s, 9.2 +/- 2.8 m/s, and 7.1 +/- 1.7 m/s, respectively, p < 0.001, analysis of variance). CONCLUSIONS: In-plane PCMRI permits determination of PWV in multiple aortic locations in a single acquisition. Progressive fragmentation of elastic fibers and alterations in the regulation of vascular tone may result in an age-related, regional increase in PWV primarily affecting the proximal aorta.

Validation of in vivo myocardial strain measurement by magnetic resonance tagging with sonomicrometry.

OBJECTIVES: This study was designed to validate strain measurements obtained using magnetic resonance tagging with spatial modulation of magnetization (SPAMM). We compared circumferential segment shortening measurements (%S) obtained using SPAMM to sonomicrometry %S in a canine model with (n = 28) and without (n = 3) coronary artery ligation. BACKGROUND: Magnetic resonance tagging enables noninvasive measurement of myocardial strain, but such strain measurements have not yet been validated in vivo. METHODS: Circumferential sonomicrometry crystal pairs were placed in apical myocardium at ischemic risk in ligation studies and in adjacent and remote myocardium. The %S was obtained from closely juxtaposed sonomicrometry and SPAMM sites. RESULTS: Paired data were available from 19 of 31 studies. Both methods distinguished remote from ischemic function effectively (p = 0.014 for SPAMM and p = 0.002 for sonomicrometry). SPAMM %S was similar to sonomicrometry %S in ischemic myocardium (2 +/- 3 vs. 0 +/- 3 p = 0.067) but was slightly higher than sonomicrometry %S in remote myocardium (11 +/- 10 vs. 7 +/- 5, p = 0.033). End-systolic (n = 30) and late systolic (n = 34) SPAMM %S correlated well with sonomicrometry %S (r = 0.84, p < 0.0001 and r = 0.88, p < 0.0001). CONCLUSIONS: Magnetic resonance tagging using SPAMM can quantitate myocardial strain in ischemic and remote myocardium. This study validates its application in scientific investigation and clinical assessment of patients with myocardial ischemia.

Combined angiotensin II receptor antagonism and angiotensin-converting enzyme inhibition further attenuates postinfarction left ventricular remodeling.

BACKGROUND: ACE inhibition (ACEI) attenuates post-myocardial infarction (MI) LV remodeling, but the effects of angiotensin II type 1 receptor (AT(1)) antagonism alone or in combination with ACEI are unclear. Accordingly, we investigated the effects of AT(1) antagonism, ACEI, and their combination in a well-characterized ovine postinfarction model. METHODS AND RESULTS: Beginning 2 days after transmural anteroapical MI, 62 sheep were treated with 1 of 5 treatment regimens: no therapy (control, n=12), standard-dose ACEI (sACEI; ramipril 10 mg/d, n=14), high-dose ACEI (hACEI; ramipril 20 mg/d, n=8), AT(1) blockade (losartan 50 mg/d, n=13), and combination therapy with sACEI+AT(1) blockade (CT; ramipril 10 mg/d+losartan 50 mg/d, n=15). MRI was performed before and 8 weeks after MI to quantify changes in LV end-diastolic and end-systolic volume indices (DeltaEDVI, DeltaESVI) and ejection fraction (DeltaEF). Change in regional percent intramyocardial circumferential shortening in noninfarcted segments adjacent to the infarct (Adj Delta%S) was measured by tagged MRI. CT resulted in the most marked blunting of LV remodeling: DeltaESVI (+1.0+/-0.4, +0.7+/-0.4, +0.6+/-0.3, +0.9+/-0.5, and +0.4+/-0.2* mL/kg); DeltaEDVI (+0.9+/-0.4, +0.7+/-0.5, +0.6+/-0.5, +0.9+/-0.5, and +0.4+/-0.3 mL/kg); DeltaEF (-24+/-7, -18+/-6, -14+/-7, -18+/-10, and -11+/-9* %); and Adj Delta%S (-8+/-4, -7+/-3, -5+/-3, -5+/-3, and -2+/-3* %) for Control, sACEI, hACEI, AT(1) blockade, and CT, respectively (*P<0.04 versus sACEI, AT(1) blockade, and control; P<0.05 versus control; P<0.002 versus AT(1) blockade and control). EDVI and ESVI at 8 weeks after MI were smallest with CT (P<0.02 versus all). CONCLUSIONS: Combination therapy with sACEI+AT(1) blockade shows promise in attenuating postinfarction LV remodeling but was not clearly superior to hACEI in the present study.

Psychosocial variables are associated with atherosclerosis risk factors among women with chest pain: the WISE study.

OBJECTIVE: We investigated associations between atherosclerosis risk factors (smoking behavior, serum cholesterol, hypertension, body mass index, and functional capacity) and psychological characteristics with suspected linkages to coronary disease (depression, hostility, and anger expression) in an exclusively female cohort. METHODS: Six hundred eighty-eight middle-aged women with chest pain warranting clinical investigation completed a comprehensive diagnostic protocol that included quantitative coronary angiography to assess coronary artery disease (CAD). Primary analyses controlled for menopausal status, age, and socioeconomic status variables (income and education). RESULTS: High depression scores were associated with a nearly three-fold risk of smoking (odds ratio (OR) = 2.8, 95% confidence interval (CI) = 1.4-5.7) after covariate adjustment, and women reporting higher depression symptoms were approximately four times more likely to describe themselves in the lowest category of functional capacity (OR = 3.7, 95% CI = 1.7-7.8). High anger-out scores were associated with a four-fold or greater risk of low high-density lipoprotein cholesterol concentration (<50 mg/dl; OR = 4.0, 95% CI = 1.4-11.1) and high low-density lipoprotein cholesterol concentration (>160 mg/dl; OR = 4.8, 95% CI = 1.5-15.7) and a larger body mass index (OR = 3.5, 95% CI = 1.1-10.8) after covariate adjustment. CONCLUSIONS: These results demonstrate consistent and clinically relevant relationships between psychosocial factors and atherosclerosis risk factors among women and may aid our understanding of the increased mortality risk among women reporting high levels of psychological distress.

Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study.

BACKGROUND: Chest pain in the absence of obstructive coronary artery disease (CAD) is common in women; it is frequently associated with debilitating symptoms and repeated evaluations and may be caused by coronary microvascular dysfunction. However, the prevalence and determinants of microvascular dysfunction in these women are uncertain. METHODS: We measured coronary flow velocity reserve (coronary velocity response to intracoronary adenosine) to evaluate the coronary microvasculature and risk factors for atherosclerosis in 159 women (mean age, 52.9 years) with chest pain and no obstructive CAD. All women were referred for coronary angiography to evaluate their chest pain as part of the Women's Ischemia Syndrome Evaluation (WISE) study. RESULTS: Seventy-four (47%) women had subnormal (<2.5) coronary flow velocity reserve suggestive of microvascular dysfunction (mean, 2.02 +/- 0.38); 85 (53%) had normal reserve (mean, 3.13 +/- 0.64). Demographic characteristics, blood pressure, ventricular function, lipid levels, and reproductive hormone levels were not significantly different between women with normal and those with abnormal microvascular function. Postmenopausal hormone use within 3 months was significantly less prevalent among those with microvascular dysfunction (40% vs 60%, P =.032). Age and number of years past menopause correlated with flow velocity reserve (r = -0.18, P =.02, and r = -0.30, P <.001, respectively). No significant associations were identified between flow velocity reserve and lipid and hormone levels, blood pressure, and left ventricular ejection fraction. CONCLUSIONS: Coronary microvascular dysfunction is present in approximately one half of women with chest pain in the absence of obstructive CAD and cannot be predicted by risk factors for atherosclerosis and hormone levels. Therefore, the diagnosis of coronary microvascular dysfunction should be considered in women with chest pain not attributable to obstructive CAD.

Detailed angiographic analysis of women with suspected ischemic chest pain (pilot phase data from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation [WISE] Study Angiographic Core Laboratory).

The purpose of this study is to provide a contemporary qualitative and quantitative analysis of coronary angiograms from a large series of women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) study who had suspected ischemic chest pain. Previous studies have suggested that women with chest pain have a lower prevalence of significant coronary artery disease (CAD) compared with men. Detailed analyses of angiographic findings relative to risk factors and outcomes are not available. All coronary angiograms were reviewed in a central core laboratory. Quantitative measurement of percent stenosis was used to assess the presence and severity of disease. Of the 323 women enrolled in the pilot phase, 34% had no detectable, 23% had measurable but minimal, and 43% had significant ( > 50% diameter stenosis) CAD. Of those with significant CAD, most had multivessel disease. Features suggesting complex plaque were identified in < 10%. Age, hypertension, diabetes mellitus, prior myocardial infarction (MI), current hormone replacement therapy, and unstable angina were all significant, independent predictors of presence of significant disease (p < 0.05). Subsequent hospitalization for a cardiac cause occurred more frequently in those women with minimal and significant disease compared with no disease (p = 0.001). The common findings of no and extensive CAD among symptomatic women at coronary angiography highlight the need for better clinical noninvasive evaluations for ischemia. Women with minimal CAD have intermediate rates of rehospitalization and cardiovascular events, and thus should not be considered low risk.

Regional myocardial strain before and after mitral valve repair for severe mitral regurgitation.

Magnetic resonance tagging (MRI) can be used to study intramyocardial trains in human in vivo. We wished to determine whether patients with severe mitral regurgitation demonstrate subtle myocardial contractile dysfunction despite normal left ventricular (LV) ejection fraction (EF) and how, mitral valve repair (MVR) may preserve EF in such patients. MRI was performed on seven patients with severe mitral regurgitation (mean age +/- SD, 65+/-13 years) and normal EF day 1 (range, 0-8 days) before (Pre) and week 8+/-3 after (Post) MVR and on nine normal volunteers (mean age, 32+/-4). LV mass index (LVMI), end-diastolic and end systolic volume, mass/volume ratio, EF, and sphericity index were measured Pre and Post. Two-dimensional strain analysis of MR tagged images was performed and expressed as L1 (greatest systolic lengthening, radial in normal subjects), L2 (greatest systolic shortening, circumferential in normals), and beta (angular deviation of L1 from the radial direction). LVMI fell from 142+/-38 g/m2 Pre to 117+/-44 g/m2 Post (p < or = 0.008) as did LV end-diastolic volume (117+/-26 to 69+/-12 ml, p < or = 0.003), whereas EF remained unchanged (59+/-7% at both time points). LV mass/volume ratio increasedfrom 2.2+/-0.3 g/ml Pre to 3.1+/-0.4 g/ml Post (p < or = 0.02) and sphericity index fell from 0.86+/-0.10 to 0.71+/-0.13 (p = 0.02). In the short axis, L1 was greater in patients with mitral regurgitation than normal subjects (19+/-9% vs 16+/-6%, p < or = 0.003) and tended to increase further after MVR (21+/-8%, p < or = 0.06 vs. Pre). Beta was abnormal in mitral regurgitation (19+/-8 vs. 12+/-8 degrees in control subjects, p < 0.0001) and remained abnormal after MVR (19+/-9 degrees). L2 in the short axis was depressed in mitral regurgitation compared with control subjects (12+/-6% vs. 21+/-6%, p < or = 0.001) and was further depressed after MVR (9+/-7%, p < 0.001 vs. Pre). As detected by MRI, regional myocardial strains are abnormal in severe mitral regurgitation despite normal EF, characterized by increased short-axis systolic lengthening that is abnormally directed and by reduced shortening. After MVR, the further increase in short-axis lengthening may preserve EF despite its abnormal direction and a fall in shortening. The increase in short-axis lengthening may be due in part to the reduction in LV sphericity after MVR.

Weight cycling and high-density lipoprotein cholesterol in women: evidence of an adverse effect: a report from the NHLBI-sponsored WISE study. Women's Ischemia Syndrome Evaluation Study Group.

OBJECTIVES: We undertook an analysis of weight cycling, coronary risk factors and angiographic coronary artery disease (CAD) in women. BACKGROUND: The effect of weight cycling on cardiovascular mortality and morbidity is controversial, and the impact of weight cycling on cardiovascular risk factors is unclear. METHODS: This is a cross-sectional population study of 485 women with coronary risk factors undergoing coronary angiography for evaluation of suspected myocardial ischemia enrolled in the Women's Ischemia Syndrome Evaluation (WISE). Reported lifetime weight cycling-defined as voluntary weight loss of at least 10 lbs at least 3 times--coronary risk factors including core laboratory determined blood lipoproteins and CAD, as determined by a core angiographic laboratory, are the main outcome measures. RESULTS: Overall, 27% of women reported weight cycling--19% cycled 10 to 19 lbs, 6% cycled 20 to 49 lbs, and 2% cycled 50+ lbs. Reported weight cycling was associated with 7% lower high-density lipoprotein cholesterol (HDL-C) levels in women (p = 0.01). The HDL-C effect was directly related to the amount of weight cycled with women who lost > or = 50 lbs/cycle having HDL-C levels 27% lower than noncyclers (p = 0.0025). This finding was independent of other HDL-C modulators, including estrogen status, physical activity level, alcohol intake, body mass index, diabetes, beta-blocker use, cigarette smoking and race. Weight cycling was not associated with an increased prevalence of CAD in this population. CONCLUSIONS: Weight cycling is associated with lower HDL-C in women of a magnitude that is known to be associated with an increased risk of cardiac events as demonstrated in prior clinical trials.

Effect of general anesthesia on the severity of mitral regurgitation by transesophageal echocardiography.

The effect of general anesthesia on the severity of mitral regurgitation (MR) was examined in 43 patients with moderate or severe MR who underwent preoperative and intraoperative transesophageal echocardiography. Systolic blood pressure, mean arterial pressure, and left ventricular end-diastolic and end-systolic dimensions were significantly lower during the intraoperative study, reflecting altered loading conditions. The mean color Doppler jet area and mean vena contracta decreased and the mean pulmonary venous flow pattern changed from reversed to blunted, reflecting a significant reduction in the severity of MR. Overall, 22 of the 43 patients (51%) improved at least 1 MR severity grade when assessed under general anesthesia. Thus, intraoperative transesophageal echocardiography may significantly underestimate the severity of MR. A thorough preoperative assessment is preferable when deciding whether to perform mitral valve surgery.

Characterization of signal properties in atherosclerotic plaque components by intravascular MRI.

Magnetic resonance imaging (MRI) is capable of distinguishing between atherosclerotic plaque components solely on the basis of biochemical differences. However, to date, the majority of plaque characterization has been performed by using high-field strength units or special coils, which are not clinically applicable. Thus, the purpose of the present study was to evaluate MRI properties in histologically verified plaque components in excised human carotid endarterectomy specimens with the use of a 5F catheter-based imaging coil, standard acquisition software, and a clinical scanner operating at 0.5 T. Human carotid endarterectomy specimens from 17 patients were imaged at 37 degrees C by use of an opposed solenoid intravascular radiofrequency coil integrated into a 5F double-lumen catheter interfaced to a 0.5-T General Electric interventional scanner. Cross-sectional intravascular MRI (156x250 microm in-plane resolution) that used different imaging parameters permitted the calculation of absolute T1and T2, the magnetization transfer contrast ratio, the magnitude of regional signal loss associated with an inversion recovery sequence (inversion ratio), and regional signal loss in gradient echo (gradient echo-to-spin echo ratio) in plaque components. Histological staining included hematoxylin and eosin, Masson's trichrome, Kossa, oil red O, and Gomori's iron stain. X-ray micrographs were also used to identify regions of calcium. Seven plaque components were evaluated: fibrous cap, smooth muscle cells, organizing thrombus, fresh thrombus, lipid, edema, and calcium. The magnetization transfer contrast ratio was significantly less in the fibrous cap (0.62+/-13) than in all other components (P<0.05) The inversion ratio was greater in lipid (0.91+/-0.09) than all other components (P<0.05). Calcium was best distinguished by using the gradient echo-to-spin echo ratio, which was lower in calcium (0.36+/-0.2) than in all plaque components, except for the organizing thrombus (P<0.04). Absolute T1 (range 300+/-140 ms for lipid to 630+/-321 ms for calcium) and T2 (range 40+/-12 ms for fresh thrombus to 59+/-21 ms for smooth muscle cells) were not significantly different between groups. In vitro intravascular MRI with catheter-based coils and standard software permits sufficient spatial resolution to visualize major plaque components. Pulse sequences that take advantage of differences in biochemical structure of individual plaque components show quantitative differences in signal properties between fibrous cap, lipid, and calcium. Therefore, catheter-based imaging coils may have the potential to identify and characterize those intraplaque components associated with plaque stability by use of existing whole-body scanners.

Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms.

BACKGROUND: After hospitalization for chest pain, women are more likely than men to have normal coronary-artery angiograms. In such women, myocardial ischemia in the absence of clinically significant coronary-artery obstruction has long been suspected. Most methods for the detection of the metabolic effects of myocardial ischemia are highly invasive. Phosphorus-31 nuclear magnetic resonance (31P-NMR) spectroscopy is a noninvasive technique that can directly measure high-energy phosphates in the myocardium and identify metabolic evidence of ischemia. METHODS: We enrolled 35 women who were hospitalized for chest pain but who had no angiographically significant coronary-artery obstructions and 12 age- and weight-matched control women with no evidence of heart disease. Myocardial high-energy phosphates were measured with 31P-NMR spectroscopy at 1.5 tesla before, during, and after isometric handgrip exercise at a level that was 30 percent of the maximal voluntary grip strength. We measured the change in the ratio of phosphocreatine to ATP during exercise. RESULTS: Seven (20 percent) of the 35 women with chest pain and no angiographically significant stenosis had decreases in the phosphocreatine:ATP ratio during exercise that were more than 2 SD below the mean value in the control subjects without chest pain. There were no significant differences between the two groups with respect to hemodynamic variables at rest and during exercise, risk factors for ischemic heart disease, findings on magnetic resonance imaging and radionuclide perfusion studies of the heart, or changes in brachial flow during the infusion of acetylcholine. CONCLUSIONS: Our results provide direct evidence of an abnormal metabolic response to handgrip exercise in at least some women with chest pain consistent with the occurrence of myocardial ischemia but no angiographically significant coronary stenoses. The most likely cause is microvascular coronary artery disease.

Global alterations in mechanical function in healed reperfused first anterior myocardial infarction.

Two-dimensional analysis techniques were applied to breathhold magnetic resonance (MR) tagged images in humans to better understand left ventricular (LV) mechanics 8 weeks after large reperfused first anterior myocardial infarction (MI). Eighteen patients (aged 51 +/- 13 yr, 15 men) were studied 8 +/- 1 weeks after first anterior MI as were 9 volunteers, (aged 30 +/- 3, 7 men). Breathhold MR myocardial tagging was performed with short-axis images spanning the LV from apex to base. Myocardial deformation was analyzed from apical, mid-LV, and basal slices using two-dimensional analytic techniques and expressed as L1 (greatest systolic lengthening), L2 (greatest systolic shortening), and beta (angular deviation of L1 from the radial direction). LV ejection fraction (EF) by MR imaging in the patients after MI was 45 +/- 15%. The apex and midventricle in patients demonstrated reduced L1 and L2 and increased beta compared with normal subjects with the greatest abnormalities at the apex, as expected in anterior infarction. However, in addition, basal L1 was lower than normal subjects (10 +/- 6% versus 19 +/- 7%, p < 0.0001) as was L2 (14 +/- 7% versus 17 +/- 6%, p < 0.04). Beta was greater than normal at the base (23 +/- 20 degrees and 14 +/- 10 degrees, p < 0.02). L2 correlated significantly with EF in the patient group (EF = 2.6 x L2 + 7, r = 0.68, p < 0.002). After healing of reperfused first anterior MI, maximal lengthening and maximal shortening and the orientation of maximal strains are abnormal throughout the left ventricle, including mild abnormalities at the base. This suggests more diffuse abnormalities in regional mechanical function than simply within the zone of healed infarction.

MRI myocardial tagging.

MRI myocardial tagging is now a well-developed method for evaluation of regional myocardial contraction. A series of progressively more refined imaging strategies, combined with advances in analytic strategies have provided a strong armamentarium of methods. Important insights into normal human physiology of left ventricular systolic and diastolic function have been developed using one-dimensional, two-dimensional and three-dimensional analyses of myocardial deformation. In disease states, improved understanding and detection of early alterations in myocardial function in hypertensive heart disease has been possible. In addition, improved understanding of effects of ischemia and infarction on regional function has been possible. Further, after acute myocardial infarction, clearer definition of the natural history of contractile dysfunction in the infarct region and the zone adjacent to the infarct have been possible. Similarly, effects on regional function of a number of important pharmacologic agents used for treatment, such as angiotensin converting enzyme inhibitors, beta blockers and angiotensin receptor blockers have been characterized. In the cardiomyopathies, myocardial tagging has permitted more reliable assessment of heterogeneity of segmental function, especially in hypertrophic cardiomyopathy. Finally, initial applications of myocardial tagging to assessment of right ventricular regional function in hypertrophied hearts with and without major congenital abnormalities have generated advances in understanding of effects of hypertrophy on right ventricular function.J. Magn. Reson. Imaging 1999;10:609-616.

Beta-blockade improves adjacent regional sympathetic innervation during postinfarction remodeling.

The effect of beta-blockade on left ventricular (LV) remodeling, when added to angiotensin-converting enzyme inhibition (ACEI) after anterior myocardial infarction (MI), is incompletely understood. On day 2 after coronary ligation-induced anteroapical infarction, 17 sheep were randomized to ramipril (ACEI, n = 8) or ramipril and metoprolol (ACEI-beta, n = 9). Magnetic resonance imaging was performed before and 8 wk after MI to measure changes in LV end-diastolic, end-systolic, and stroke volume indexes, LV mass index, ejection fraction (EF), and regional percent intramyocardial circumferential shortening. (123)I-labeled m-iodobenzylguanidine (MIBG) and fluorescent microspheres before and after adenosine were infused before death at 8 wk post-MI for quantitation of sympathetic innervation, blood flow, and blood flow reserve in adjacent and remote noninfarcted regions. Infarct size, regional blood flow, blood flow reserve, and the increase in LV mass and LV end-diastolic and end-systolic volume indexes were similar between groups. However, EF fell less over the 8-wk study period in the ACEI-beta group (-13 +/- 11 vs. -22 +/- 4% in ACEI, P < 0.05). The ratio of adjacent to remote region (123)I-MIBG uptake was greater in ACEI-beta animals than in the ACEI group (0.93 +/- 0.06 vs. 0.86 +/- 0.07, P < 0.04). When added to ACE inhibition after transmural anteroapical MI, beta-blockade improves EF and adjacent regional sympathetic innervation but does not alter LV size.

The Women's Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report.

OBJECTIVES: The Women's Ischemia Syndrome Evaluation (WISE) is a National Heart, Lung and Blood Institute-sponsored, four-center study designed to: 1) optimize symptom evaluation and diagnostic testing for ischemic heart disease; 2) explore mechanisms for symptoms and myocardial ischemia in the absence of epicardial coronary artery stenoses, and 3) evaluate the influence of reproductive hormones on symptoms and diagnostic test response. BACKGROUND: Accurate diagnosis of ischemic heart disease in women is a major challenge to physicians, and the role reproductive hormones play in this diagnostic uncertainty is unexplored. Moreover, the significance and pathophysiology of ischemia in the absence of significant epicardial coronary stenoses is unknown. METHODS: The WISE common core data include demographic and clinical data, symptom and psychosocial variables, coronary angiographic and ventriculographic data, brachial artery reactivity testing, resting/ambulatory electrocardiographic monitoring and a variety of blood determinations. Site-specific complementary methods include physiologic and functional cardiovascular assessments of myocardial perfusion and metabolism, ventriculography, endothelial vascular function and coronary angiography. Women are followed for at least 1 year to assess clinical events and symptom status. RESULTS: In Phase I (1996-1997), a pilot phase, 256 women were studied. These data indicate that the WISE protocol is safe and feasible for identifying symptomatic women with and without significant epicardial coronary artery stenoses. CONCLUSIONS: The WISE study will define contemporary diagnostic testing to evaluate women with suspected ischemic heart disease. Phase II (1997-1999) is ongoing and will study an additional 680 women, for a total WISE enrollment of 936 women. Phase III (2000) will include patient follow-up, data analysis and a National Institutes of Health WISE workshop.

Dobutamine stress echocardiography in women with chest pain. Pilot phase data from the National Heart, Lung and Blood Institute Women's Ischemia Syndrome Evaluation (WISE).

OBJECTIVES: The aim of this project was to assess the utility of dobutamine stress echocardiography (DSE) for evaluation of women with suspected ischemic heart disease. BACKGROUND: Most investigations addressing efficacy of diagnosis and treatment of coronary artery disease (CAD) have been performed in predominantly male populations. As part of the Women's Ischemia Syndrome Evaluation (WISE) study, DSE was assessed in women participating at the University of Florida clinical site. METHODS: Women with chest pain or other symptoms suggestive of myocardial ischemia and clinically indicated coronary angiography were eligible for the WISE study. Enrolled subjects underwent DSE using a modified protocol. Coronary stenosis was assessed by core laboratory quantitative coronary angiography (QCA). RESULTS: The 92 women studied ranged in age from 34 to 82 years (mean 57.5). All women had > or = 1 major risk for CAD, and most (89, 97%) had > or = 2 risk factors. In 78 women (85%), left ventricular wall motion was normal at baseline and during peak infusion. The remaining 14 women had wall motion abnormalities during DSE. By QCA, 25 women (27%) had > or = 50% coronary stenosis, including 10 with single-vessel obstruction. Dobutamine stress echocardiography was abnormal in 10 of these 25 women, yielding overall sensitivity of 40%, and 60% for multivessel stenosis. Exclusion of women with inadequate heart rate response yielded overall sensitivity of 50%, and 81.8% for multivessel stenosis. Dobutamine stress echocardiography was normal in 54 of the 67 women with < 50% coronary narrowing, specificity 80.6%. CONCLUSIONS: Dobutamine stress echocardiography reliably detects multivessel stenosis in women with suspected CAD. However, DSE is usually negative in women with single-vessel stenosis, and in the larger subset without coronary stenosis. Ongoing protocols of the WISE study are expected to improve diagnostic accuracy in women with single-vessel disease, as well as provide important data in the substantial number of women with chest pain but without epicardial coronary artery stenosis.

Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study.

OBJECTIVES: We sought to develop and validate a definition of coronary microvascular dysfunction in women with chest pain and no significant epicardial obstruction based on adenosine-induced changes in coronary flow velocity (i.e., coronary velocity reserve). BACKGROUND: Chest pain is frequently not caused by fixed obstructive coronary artery disease (CAD) of large vessels in women. Coronary microvascular dysfunction is an alternative mechanism of chest pain that is more prevalent in women and is associated with attenuated coronary volumetric flow augmentation in response to hyperemic stimuli (i.e., abnormal coronary flow reserve). However, traditional assessment of coronary volumetric flow reserve is time-consuming and not uniformly available. METHODS: As part of the Women's Ischemia Syndrome Evaluation (WISE) study, 48 women with chest pain and normal coronary arteries or minimal coronary luminal irregularities (mean stenosis = 7%) underwent assessment of coronary blood flow reserve and coronary flow velocity reserve. Blood flow responses to intracoronary adenosine were measured using intracoronary Doppler ultrasonography and quantitative angiography. RESULTS: Coronary volumetric flow reserve correlated with coronary velocity reserve (Pearson correlation = 0.87, p < 0.001). In 29 (60%) women with abnormal coronary microcirculation (mean coronary flow reserve = 1.84), adenosine increased coronary velocity by 89% (p < 0.001) but did not change coronary cross-sectional area. In 19 (40%) women with normal microcirculation (mean flow reserve = 3.24), adenosine increased coronary velocity and area by 179% (p < 0.001) and 17% (p < 0.001), respectively. A coronary velocity reserve threshold of 2.24 provided the best balance between sensitivity and specificity (90% and 89%, respectively) for the diagnosis of microvascular dysfunction. In addition, failure of the epicardial coronary to dilate at least 9% was found to be a sensitive (79%) and specific (79%) surrogate marker of microvascular dysfunction. CONCLUSIONS: Coronary flow velocity response to intracoronary adenosine characterizes coronary microvascular function in women with chest pain in the absence of obstructive CAD. Attenuated epicardial coronary dilation response to adenosine may be a surrogate marker of microvascular dysfunction in women with chest pain and no obstructive CAD.

Early contrast-enhanced MRI predicts late functional recovery after reperfused myocardial infarction.

BACKGROUND: We have observed 3 abnormal patterns on contrast-enhanced MRI early after reperfused myocardial infarction (MI): (1) absence of normal first-pass signal enhancement (HYPO), (2) normal first pass signal followed by hyperenhanced signal on delayed images (HYPER), or (3) both absence of normal first-pass enhancement and delayed hyperenhancement (COMB). This study examines the association between these patterns in the first week after MI and late recovery of myocardial contractile function by use of magnetic resonance myocardial tissue tagging. METHODS AND RESULTS: Seventeen patients (14 men) with a mean age of 53+/-12 years were studied after a reperfused first MI. Contrast-enhanced images were acquired immediately after bolus administration of gadolinium and 7+/-2 minutes later. Tagged images were acquired at weeks 1 and 7. Circumferential segment shortening (%S) was measured in regions displaying HYPER, COMB, or HYPO contrast patterns and in remote regions (REMOTE) at weeks 1 and 7. At week 1, %S was depressed in HYPER, COMB, and HYPO (9+/-8%, 7+/-6%, and 5+/-4%, respectively) and were less than REMOTE (18+/-6%, P<0.003). However, in HYPER, %S improved at week 7 from 9+/-8% to 18+/-5% (P<0.001 versus week 1). In contrast, HYPO did not improve significantly (5+/-4% to 6+/-3%, P=NS) and COMB tended to improve 7+/-6% to 11+/-6% (P=0.06). CONCLUSIONS: HYPER has partially reversible dysfunction and represents predominantly viable myocardium. COMB shows borderline improvement and likely contains an admixture of viable and necrotic myocardium. HYPO shows little functional improvement at 7 weeks, presumably because of irreversible myocardial damage.