Ultrasound in decompression research: fundamentals, considerations, and future technologies.

It is widely accepted that bubbles are a necessary but insufficient condition for the development of decompression sickness. However, open questions remain regarding the precise formation and behavior of these bubbles after an ambient pressure reduction (decompression), primarily due to the inherent difficulty of directly observing this phenomenon in vivo. In decompression research, information about these bubbles after a decompression is gathered via means of ultrasound acquisitions. The ability to draw conclusions regarding decompression research using ultrasound is highly influenced by the variability of the methodologies and equipment utilized by different research groups. These differences play a significant role in the quality of the data and thus the interpretation of the results. The purpose of this review is to provide a technical overview of the use of ultrasound in decompression research, particularly Doppler and brightness (B)-mode ultrasound. Further, we will discuss the strengths and limitations of these technologies and how new advancements are improving our ability to understand bubble behavior post-decompression.

Hemodynamics and Prognostic Impact of Concomitant Mitral Stenosis in Patients Undergoing Surgical or Transcatheter Aortic Valve Replacement for Aortic Stenosis.

BACKGROUND: Mitral stenosis frequently coexists in patients with severe aortic stenosis. Mitral stenosis severity evaluation is challenging in the setting of combined aortic stenosis and mitral stenosis because of hemodynamic interactions between the 2 valve lesions. The impact of aortic valve replacement (AVR) for severe aortic stenosis on mitral stenosis is unknown. This study aimed to assess the effect of AVR on mitral stenosis hemodynamics and the clinical outcomes of patients with severe aortic stenosis with and without mitral stenosis. METHODS: We retrospectively investigated patients who underwent surgical AVR or transcatheter AVR for severe aortic stenosis from 2008 to 2015. Mean transmitral gradient by Doppler echocardiography ≥4 mm Hg was identified as mitral stenosis; patients were then stratified according to mitral valve area (MVA, by continuity equation) as >2.0 cm2 or ≤2.0 cm2. MVA before and after AVR in patients with mitral stenosis were evaluated. Clinical outcomes of patients with and without mitral stenosis were compared using 1:2 matching for age, sex, left ventricular ejection fraction, method of AVR (surgical AVR versus transcatheter AVR) and year of AVR. RESULTS: Of 190 patients with severe aortic stenosis and mitral stenosis (age 76±9 years, 42% men), 184 were matched with 362 with severe aortic stenosis without mitral stenosis. Among all mitral stenosis patients, the mean MVA increased after AVR by 0.26±0.59 cm2 (from 2.00±0.50 to 2.26±0.62 cm2, P<0.01). MVA increased in 105 (55%) and remained unchanged in 34 (18%). Indexed stroke volume ≤45 mL/m2 (odds ratio [OR] 2.40; 95% CI, 1.15-5.01; P=0.020) and transcatheter AVR (OR, 2.36; 95% CI, 1.17-4.77; P=0.017) were independently associated with increase in MVA. Of 107 with significant mitral stenosis (MVA ≤2.0 cm2), MVA increased to >2.0 cm2 after AVR in 52 (49%, pseudo mitral stenosis) and remained ≤2.0 cm2 in 55 (51%, true mitral stenosis). During follow-up of median 2.9 (0.7-4.9) years, true mitral stenosis was an independent predictor of all-cause mortality (adjusted hazard ratio, 1.88; 95% CI, 1.20-2.94; P<0.01). CONCLUSIONS: MVA improved after AVR in nearly half of patients with severe aortic stenosis and mitral stenosis. MVA remained ≤2.0 cm2 (true mitral stenosis) in nearly half of patients with severe aortic stenosis and significant mitral stenosis; this was associated with worse survival among patients undergoing AVR for severe aortic stenosis.

Prognostic significance of the echocardiographic estimate of pulmonary hypertension and of right ventricular dysfunction in acute decompensated heart failure. A pilot study in HFrEF patients.

BACKGROUND: Mortality following an admission for acute decompensated heart failure (ADHF) is high and risk stratification in this context remains a challenge. The objective of the present study was to assess whether a simple echocardiographic assessment of pulmonary hypertension (PH) and/or of right ventricular (RV) dysfunction is associated with cardiovascular events in a 1-year follow-up after hospital discharge. METHODS AND RESULTS: The present prospective longitudinal study included 214 patients admitted to hospital with a cardiologist-adjudicated diagnosis of ADHF and a left ventricular ejection fraction (LVEF) at echocardiography < 40%. Echocardiography was performed at admission and at discharge and included pulmonary artery systolic pressure (PASP) and RV function as defined by the tricuspid annular plane systolic displacement (TAPSE). The primary end-point was the combination of all-cause mortality and re-hospitalization for worsening heart failure at 1 year after hospital discharge. During an average follow-up period of 230 ±â€¯130 days, 40 patients died and 41 patients underwent re-hospitalization due to ADHF. At multivariate analysis the independent predictors were LVEF, PASP at discharge and creatinine plasma levels (all p < 0.001). At ROC analysis the best threshold of PASP to discriminate low-risk from high-risk patients was 40 mm Hg. CONCLUSIONS: In ADHF patients with reduced LVEF, PH at discharge is a pivotal prognostic feature to predict morbidity/mortality within the first year after the acute episode.

Advanced Age Attenuates Left Ventricular Filling Efficiency Quantified Using Vortex Formation Time: A Study of Octogenarians With Normal Left Ventricular Systolic Function Undergoing Coronary Artery Surgery.

OBJECTIVE: Blood flow across the mitral valve during early left ventricular (LV) filling produces a 3-dimensional rotational fluid body, known as a vortex ring, that enhances LV filling efficiency. Diastolic dysfunction is common in elderly patients, but the influence of advanced age on vortex formation is unknown. The authors tested the hypothesis that advanced age is associated with a reduction in LV filling efficiency quantified using vortex formation time (VFT) in octogenarians undergoing coronary artery bypass graft (CABG) surgery. DESIGN: Observational study. SETTING: Veterans Affairs medical center. PARTICIPANTS: After institutional review board approval, octogenarians (n = 7; 82 ± 2 year [mean ± standard deviation]; ejection fraction 56% ± 7%) without valve disease or atrial arrhythmias undergoing CABG were compared with a younger cohort (n = 7; 55 ± 6 year; ejection fraction 57% ± 7%) who were undergoing coronary revascularization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were monitored using radial and pulmonary arterial catheters and transesophageal echocardiography. Peak early LV filling (E) and atrial systole (A) blood flow velocities and their corresponding velocity-time integrals were obtained using pulse-wave Doppler echocardiography to determine E/A, atrial filling fraction (ß), and E wave deceleration time. Pulse-wave Doppler also was used to measure pulmonary venous blood flow during systole and diastole. Mitral valve diameter (D) was calculated as the average of major and minor axis lengths obtained in the midesophageal LV bicommissural and long-axis transesophageal echocardiography imaging planes, respectively. VFT was calculated as 4 × (1 - ß) × SV/(πD3), where SV is the stroke volume measured using thermodilution. Systemic and pulmonary hemodynamics, LV diastolic function, and VFT were determined during steady-state conditions 30 minutes before cardiopulmonary bypass. A delayed relaxation pattern of LV filling (E/A 0.81 ± 0.16 v 1.29 ± 0.19, p = 0.00015; ß 0.44 ± 0.05 v 0.35 ± 0.03, p = 0.0008; E wave deceleration time 294 ± 58 v 166 ± 28 ms, p < 0.0001; ratio of peak pulmonary venous systolic and diastolic blood flow velocity 1.42 ± 0.23 v 1.14 ± 0.20, p = 0.0255) was observed in octogenarians compared with younger patients. Mitral valve diameter was similar between groups (2.7 ± 0.2 and 2.6 ± 0.2 cm, respectively, in octogenarians v younger patients, p = 0.299). VFT was reduced in octogenarians compared with younger patients (3.0 ± 0.9 v 4.5 ± 1.2; p = 0.0171). An inverse correlation between age and VFT was shown using linear regression analysis (VFT = -0.0627 × age + 8.24; r2 = 0.408; p = 0.0139). CONCLUSION: The results indicate that LV filling efficiency quantified using VFT is reduced in octogenarians compared with younger patients undergoing coronary artery bypass grafting.

Aortic stenosis and aortic regurgitation express different titin isoforms: Differences and relationships with functional and geometric characteristics.

Background-Titin represents an important biomechanical sensor which determines compliance and diastolic/systolic function of the left ventricle (LV). To assess the different titin-isoform expression and the relationships with functional and geometric patterns, we analyzed titin-isoform expression and cardiomyocytes contractile function in myocardial biopsy samples of patients undergoing aortic valve replacement (AVR) for aortic stenosis (AS) and for aortic regurgitation (AR). Method -Specimens, collected from the LV of 35 with AS and 35 with AR undergoing AVR were analyzed for titin-isoform expression and cardiomyocytes force measurement. Ten donor hearts were analyzed as controls for normal values. Results were implemented with preoperative geometry and function assessed by Doppler echocardiography. Results-Compared to controls, N2BA/N2B titin-isoforms ratio was reduced to 0.24 in AS (p < 0.001) but increased to 0.51 in AR (p < 0.001). N2BA/N2B titin-isoforms ratio was further reduced in 8 patients with severe (restrictive) diastolic dysfunction (0.17 ±â€¯0.03, p < 0.001) but was increased in patients with severe systolic dysfunction (0.58 ±â€¯0.07, p < 0.001). As compared to controls, Fpasive was higher in AS (6.7 ±â€¯0.2 vs 4.4 ± 0.4 kN/m2, p < 0.001) but was lower in AR (3.7 ±â€¯0.2 vs 4.4 ±â€¯0.4 kN/m2, p < 0.001). Total force was comparable. Fpassive was significantly higher in AS patients with severe than with moderate LV diastolic dysfunction (7.1 ± 0.5 vs 6.6. ±â€¯0.6, p = 0.004). Conclusions-titin-isoform expression differs in AS and AR as adaptive response to different pathophysiologic scenarios. Co-expressing isoforms at varying ratios results in modulation of the passive mechanical behavior of the LV at different degree of dysfunction and allows for compensative adjustment of the diastolic/systolic properties of the myocardium.

Invasive and noninvasive hemodynamic assessment in adults with Fontan palliation.

BACKGROUND/OBJECTIVES: Although echocardiographic-Doppler cardiac index (CI) assessment is widely used to guide heart failure management in patients with biventricular circulation, this application has not been studied in the Fontan population. The objective of this study was to: (1) determine the correlation between Doppler and cardiac catheterization CI calculation; (2) determine the association between Doppler CI and the occurrence of Fontan failure. METHODS: Retrospective review of adult Fontan patients followed at Mayo Clinic Adult Congenital Heart Disease program, 1994-2015. Inclusion criteria were: systemic left ventricle and echocardiogram and cardiac catheterization performed within the same week. Fontan failure was defined as a composite of all-cause mortality, heart transplantation listing, and palliative care. RESULTS: 59 patients (age 29±6years; men 32[54%]) underwent 97 studies. Of the 59, 41[69%] had atriopulmonary Fontan and 12 (20%) had cirrhosis. Compared to patients without cirrhosis, patients with cirrhosis had higher Doppler CI (3.6±0.6 vs 2.8±0.4L/min∗m2, p=0.039); Fick CI (3.3 [2.5-3.7] vs 2.4 [1.6-3.1] L/min/m2, p=0.028); lower systemic vascular resistance (20±3 vs 25±4 WU∗m2, p=0.04). There was a positive correlation between Doppler and Fick CI (r=0.52; p<0.0001). Fontan failure occurred in 13 patients (22%) within 7.5±2.1years. In patients without cirrhosis, Fick CI and Doppler CI <2.5L/min/m2 were associated with Fontan failure (odds ratio [OR] 1.58, p=0.046) and (OR 1.43, p=0.051) respectively. CONCLUSIONS: Doppler CI assessment in feasible in a selected group of Fontan patients and it is predictive of clinical outcomes. The application of this concept in systemic right ventricles deserves further research.

Severe aortic stenosis patients with preserved ejection fraction according to flow and gradient classification: Prevalence and outcomes.

BACKGROUND: Clinicians often encounter patients with apparently discordant echocardiographic findings, severe aortic stenosis (SAS) defined by aortic valve area (AVA) despite a low mean gradient. A new classification according to flow state and pressure gradient has been proposed. We sought to assess the prevalence, characteristics and outcomes of patients with asymptomatic SAS with preserved left-ventricular ejection fraction (LVEF) according to flow and gradient. METHODS AND RESULTS: In total 442 patients with SAS (AVAi<0.6 cm2/m2) and LVEF ≥50% (mean age 80+11years, 54,5% female) were included. Patients were classified according to flow state (≥ or <35ml/m2) and mean pressure gradient (≥ or <40mmHg): Low Flow/Low Gradient (LF/LG): 21.3%(n=94); Normal Flow/Low Gradient (NF/LG): 32.1%(n=142); Low Flow/High Gradient (LF/HG): 6.8%(n=30); Normal Flow/High Gradient (NF/HG): 39,8%(n=176). Mean follow-up time was 20.5months (SD=10.3). Primary combined endpoint was cardiovascular mortality and hospital admission for SAS related symptom, secondary endpoint was aortic valve replacement (AVR), comparing HG group to LF/LG group. During follow-up 17 (18%) of LF/LG patients and 21 (10.2%) of HG patients met the primary endpoint. A lower free of event survival (cardiovascular mortality and hospital admission) was observed in patients with LF/LG AS (Breslow, p=0.002). Significant differences were noted between groups with a lower AVR free survival in the LF/LG group compared to HG groups (Breslow, p=0.002). CONCLUSIONS: Our study confirms the high prevalence and worse prognosis of LF/LG SAS. Clinicians must be aware of this entity to ensure appropriate patient management.

Prevalence of diastolic function and clinical impact on long-term outcome in takotsubo cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy (TTC) is a syndrome characterized by transient regional systolic dysfunction of the left ventricle (LV). However, far fewer reports focused on the prevalence of left ventricular diastolic function (DF) and its impact on an adverse prognosis in TTC. METHODS: From January 2005 to October 2014, 205 consecutive TTC patients (mean age, 70±12years; 95% female) were studied. The patients underwent transthoracic echocardiography at the acute phase and recovery phase (mean, 38±16days after admission). RESULTS: DF was labeled as normal, mild, moderate and severe. At the acute phase, Abnormal DF was present in 108 patients (53%), and left ventricular ejection fraction (LVEF) <50% in 156 patients (76%). At the recovery phase, DF was unchanged for 104 patients (51%), 44 patients (21%) had worsened, 57 patients (28%) had improved in DF grade. 25 patients (12%) had an LVEF <50%. During 2years of follow-up, 34 patients developed clinical adverse events. Kaplan-Meier analysis estimated that the subgroup with unimproved DF and LVEF <50% at recovery phase had the worst 2-year survival. In multivariable analysis, unimproved DF with LVEF <50% and heart rate (HR) remained predictors of clinical adverse events. CONCLUSIONS: The current study demonstrated that consideration of both change of DF and LVEF allows identification of subgroups with divergent long-term prognoses in patients with TTC, and may indicate the need for a different management in the high-risk TTC patients.

Early changes of left ventricular filling pattern after reperfused ST-elevation myocardial infarction and doxycycline therapy: Insights from the TIPTOP trial.

AIM: Metalloproteinases inhibition by doxycycline reduces cardiac protein degradation at extracellular and intracellular level in the experimental model ischemia/reperfusion injury. Since both extracellular cardiac matrix and titin filaments inside the cardiomyocyte are responsible for the myocardial stiffness, we hypothesized that doxycycline could favorably act on left ventricular (LV) filling pressures in patients after reperfused acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Seventy-three of 110 patients of the TIPTOP trial underwent a 2D-Echo-Doppler on admission, and at pre-discharge and at 6-month after a primary PCI for STEMI and LV dysfunction. From admission to pre-discharge, LV filling changed from a high filling pressure (HFP) to a normal filling pressure (NFP) pattern in 91% of the doxycycline-group, and in 67% of the control-group. Conversely, 1% of the doxycycline-group, and 37% of the control-group changed the LV filling from NFP to HFP pattern. Overall, a pre-discharge HFP pattern was present in 4 patients (11%) of the doxycycline-group and in 13 patients (36%) of the control-group (p=0.025). The evaluation of metalloproteinases and their tissue inhibitors plasma concentrations provide possible favorable action of doxycycline. On the multivariate analyses, troponine I peak (p=0.026), doxycycline (p=0.033), and on admission to pre-discharge LVEF changes (p=0.044) were found to be associated with pre-discharge HFP pattern. Independently of their baseline LV filling behavior, the 6-month remodeling was less in patients with pre-discharge NFP pattern than in patients with HFP pattern. CONCLUSIONS: In patients with STEMI and LV dysfunction doxycycline can favorably modulate the LV filling pattern early after primary PCI.

Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.

The rapid technological developments of the past decade and the changes in echocardiographic practice brought about by these developments have resulted in the need for updated recommendations to the previously published guidelines for cardiac chamber quantification, which was the goal of the joint writing group assembled by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. This document provides updated normal values for all four cardiac chambers, including three-dimensional echocardiography and myocardial deformation, when possible, on the basis of considerably larger numbers of normal subjects, compiled from multiple databases. In addition, this document attempts to eliminate several minor discrepancies that existed between previously published guidelines.

Left atrial function by speckle-tracking echocardiography in chronic asymptomatic alcoholic patients.

Although the effects of chronic alcoholism on left ventricular (LV) systolic function are well established, diastolic impairment has been evaluated partially. In addition, there are scarce data available about the relation of LV diastolic function to either or both duration and quantity of drinking among alcoholics. The aim of the study was to evaluate the left atrial (LA) function in chronic asymptomatic alcoholic patients by using two-dimensional speckle-tracking echocardiography (2D-STE). We enrolled 30 healthy subjects (age 34.8 ± 5.8 years) and 75 asymptomatic male alcoholics (age 39.8 ± 6.5 years) divided into two groups, according to total lifetime dose of ethanol: group I, <15 kg/kg and group II, ≥15 kg/kg. In the 2D-STE analysis of the LA, strain during ventricular systole (LA-Res), during late diastole (LA-Pump) and strain rate during ventricular contraction (LA-SRs), during passive ventricular filling (LA-SRe), during active atrial contraction (LA-SRa) were obtained. Deceleration time was longer, E/A and V(p) were smaller, and E/E(m) was higher in alcoholics. Although parameters of diastolic dysfunction were comparable in alcoholic groups, LA-Res and LA-Pump were found significantly different among the alcoholics. However, there were no differences in LA-SRs and LA-SRe between the controls and alcoholic groups. LA function is reduced in chronic alcohol abuse, and heavy alcohol consumption may play an important role in LA function impairment.

Recent evolutions in pediatric and congenital echocardiography.

PURPOSE OF REVIEW: Echocardiography is the first-line diagnostic technique in patients with congenital heart disease. Recent developments include further standardization of pediatric and congenital echocardiography with general-specific and lesion-specific guidelines. New research focuses on clinical validation of echocardiographic quantitative techniques for assessing right ventricular and single ventricular function. RECENT FINDINGS: Recent guidelines include standardization of pediatric echocardiographic measurements and description of utilization of imaging techniques in patients diagnosed with tetralogy of Fallot. Description of resource utilization and organizational standards, including systems for quality assurance, are important tools for improving the diagnostic quality of pediatric echocardiographic laboratories. We highlight interesting new research on the echocardiographic assessment of right ventricular function in patients after tetralogy of Fallot repair, patients with single-ventricle physiology and pediatric cardiomyopathies. SUMMARY: Pediatric and congenital echocardiography is evolving as an important specific area within echocardiography. It is developing its own standards and quality control, and research in this field focuses on development of more quantitative methods for assessing ventricular function.

Left ventricular long-axis performance during exercise is an important prognosticator in patients with heart failure and preserved ejection fraction.

BACKGROUND: Although many prognostic variables have been reported, the risk stratification of patients with heart failure and preserved ejection fraction (HFPEF) has long been controversial due to considerable discordance. Ergometry stress echocardiography may provide a more clinical relevant evaluation in HFPEF. We aimed at evaluating the prognostic value of echocardiographic parameters during exercise in HFPEF patients. METHODS: Comprehensive echocardiographic examination with symptom-limited exercise testing on a semi-recumbent and tilting bicycle Ergometer (Lode BV, Groningen, the Netherlands) was performed on 80 consecutive HFPEF patients (aged 66±8years; 64% male). The exercise images for two-dimensional (2D) speckle tracking analysis were acquired with heart rate of 90-100bpm, while exercise images for tissue Doppler imaging (TDI) and M-mode echocardiography were stored with attainment of >85% of maximal age-predicted heart rate. All patients were followed up for 3years after stress echocardiography for all-cause mortality and/or heart failure (HF) hospitalization. RESULTS: During the follow-up, 43 (54%) patients reached the combined end point: 5 (6%) patients died, and another 38 (48%) patients experienced HF hospitalizations. Univariate predictors were: decreased resting left atrial ejection fraction (LAEF), lower peak heart rate, elevated E/e' ratio, reduced TDI myocardial velocities, and impaired 2D global longitudinal strain (GLS) during exercise. Only impaired GLS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.67 to 0.91) remained independent after multivariate analysis (p=0.008). CONCLUSIONS: More than half of the HFPEF patients died or were hospitalized for HF at 3-year follow-up and this was significantly related to impaired left ventricular long-axis function during exercise.

Effect of increasing age on the haemodynamic response to thoracic epidural anaesthesia: an observational study.

BACKGROUND: Sympathetic blockade with thoracic epidural anaesthesia (TEA) results in circulatory changes and may directly alter cardiac function. Ageing is associated with an impairment of autonomic nervous system control and a deterioration of myocardial diastolic performance. OBJECTIVES: We postulated that haemodynamic changes induced by TEA could vary with age. DESIGN: An observational study. SETTINGS: Tertiary, university hospital. PATIENTS: Thirty-five patients scheduled for pulmonary surgery and TEA stratified into three age groups: 18 to 45 years; 46 to 65 years; and at least 66 years. INTERVENTIONS: Cardiac performance was evaluated in awake patients using transthoracic echocardiography (TTE) at baseline and 45 min after institution of TEA. Intravenous volume loading was used to preserve preload. MAIN OUTCOME MEASURES: Tissue Doppler imaging (TDI) and other derived indices from TTE were used to quantify biventricular systolic and diastolic function. RESULTS: Baseline systolic and diastolic left ventricular function and right ventricular diastolic function decreased with age. After TEA, mean arterial pressure (MAP) decreased (91.2 vs. 79.2 mmHg; P < 0.001) and cardiac index increased (2.7 vs. 3.0 l min m; P = 0.005), although heart rate and Doppler-derived indices of left ventricular contractility remained unchanged. Right ventricular ejection indices increased and TDI-derived measures of diastolic performance increased for the left ventricle (LV) as well as the right ventricle (RV). With the exception of Tricuspid Annular Plane Systolic Excursion (TAPSE), which increased with increasing age (R = 0.53; P = 0.003), TEA effects on biventricular function were not influenced by age. CONCLUSION: When preload is preserved with volume loading, TEA predominantly causes systemic vasodilatation and increases global haemodynamic performance. Indices of left ventricular systolic function do not change, whereas left ventricular and right ventricular diastolic function appears to improve. The effects of TEA on right ventricular systolic function are inconclusive. Although increasing age causes a consistent decline of baseline diastolic function, the cardiovascular response to TEA is not impaired in the elderly. TRIAL REGISTRY NUMBER: EudraCT 2009-010594-20.

Improving diagnosis and treatment of women with angina pectoris and microvascular disease: the iPOWER study design and rationale.

BACKGROUND: The iPOWER study aims at determining whether routine assessment of coronary microvascular dysfunction (CMD) in women with angina and no obstructive coronary artery disease is feasible and identifies women at risk. METHODS: All women with angina referred to invasive angiographic assessment in Eastern Denmark are invited to join the study according to in- and exclusion criteria. Assessment includes demographic, clinical and psychosocial data, symptoms, electrocardiogram, blood- and urine samples and transthoracic echocardiography during rest and dipyridamol stress with measurement of coronary flow reserve (CFR) by Doppler of the left anterior descending artery. In substudies CMD will be assessed by positron emission tomography, peripheral endothelial function, magnetic resonance imaging-and computed tomography derived myocardial perfusion scans, angiographic corrected TIMI frame counts, advanced echocardiographic modalities at rest and during stress, and invasive measures of CFR and coronary vascular reactivity. The study will include 2000 women who will be followed for 5 years for cardiovascular outcomes. RESULTS: By May 2013, 1685 women have been screened, 759 eligible patients identified, 530 contacted, and 299 (56%) agreed to participate. Among the first 50 patients, Doppler CFR was successfully measured in 49 (98%). CONCLUSIONS: Among women with suspected ischemic heart disease and no obstructive coronary artery disease, non-invasive Doppler CFR is feasible as a routine assessment. The study will provide information on methods to diagnose CMD and determine the prognostic value of routine non-invasive assessment of microvascular function. Future study will provide women identified with CMD participation in interventional substudies designed to test treatment strategies.