Comprehensive Management of ANOCA, Part 1-Definition, Patient Population, and Diagnosis: JACC State-of-the-Art Review.

Angina with nonobstructive coronary arteries (ANOCA) is increasingly recognized and may affect nearly one-half of patients undergoing invasive coronary angiography for suspected ischemic heart disease. This working diagnosis encompasses coronary microvascular dysfunction, microvascular and epicardial spasm, myocardial bridging, and other occult coronary abnormalities. Patients with ANOCA often face a high burden of symptoms and may experience repeated presentations to multiple medical providers before receiving a diagnosis. Given the challenges of establishing a diagnosis, patients with ANOCA frequently experience invalidation and recidivism, possibly leading to anxiety and depression. Advances in scientific knowledge and diagnostic testing now allow for routine evaluation of ANOCA noninvasively and in the cardiac catheterization laboratory with coronary function testing (CFT). CFT includes diagnostic coronary angiography, assessment of coronary flow reserve and microcirculatory resistance, provocative testing for endothelial dysfunction and coronary vasospasm, and intravascular imaging for identification of myocardial bridging, with hemodynamic assessment as needed.

Comprehensive Management of ANOCA, Part 2-Program Development, Treatment, and Research Initiatives: JACC State-of-the-Art Review.

Centers specializing in coronary function testing are critical to ensure a systematic approach to the diagnosis and treatment of angina with nonobstructive coronary arteries (ANOCA). Management leveraging lifestyle, pharmacology, and device-based therapeutic options for ANOCA can improve angina burden and quality of life in affected patients. Multidisciplinary care teams that can tailor and titrate therapies based on individual patient needs are critical to the success of comprehensive programs. As coronary function testing for ANOCA is more widely adopted, collaborative research initiatives will be fundamental to improve ANOCA care. These efforts will require standardized symptom assessments and data collection, which will propel future large-scale clinical trials.

Hemodynamic and Mid-Term Outcomes for Transcatheter Aortic Valve Replacement in Degenerated Internally Stented Valves.

BACKGROUND: Valve-in-valve (ViV) transcatheter aortic valve replacement is indicated in patients undergoing repeat intervention for degenerative aortic valve bioprostheses. Patients with internally stented valves (ie, Mitroflow and Trifecta) are at high risk for coronary artery obstruction during ViV procedures because of valve design, as the leaflets are mounted outside the valve stent. OBJECTIVES: The aim of this study was to compare the hemodynamic and clinical outcomes of transcatheter aortic valve replacement within internally stented valves (ViV-IS) vs other surgical valves (ViV-OS). METHODS: Baseline characteristics, hemodynamic parameters, and clinical outcomes of patients who underwent ViV-IS were retrospectively collected and compared with those of patients who underwent ViV-OS. RESULTS: A total of 250 patients (65% men, median Society of Thoracic Surgeons score 4.4% [IQR: 2.2%-8.4%]) were included. Seventy-one patients (28%) underwent ViV-IS, and 179 (72%) patients underwent ViV-OS. Patients who underwent ViV-OS had better periprocedural hemodynamic status compared with those who underwent ViV-IS (median mean gradient 6 [IQR: 2-13] vs 12 [IQR: 6-16]; P < 0.001). This was not significantly different when both groups were matched on the basis of age, sex, and valve internal diameter size (median mean gradient: 18 [IQR: 13-25] for ViV-OS vs 18 [IQR: 11-24] for ViV-IS; P = 0.36). Coronary protection for potential occlusion was performed more in ViV-IS vs ViV-OS pr (79% vs 6%, respectively; P < 0.001). Patients who underwent ViV-IS had a higher risk for coronary occlusion, requiring stent deployment, compared with those who underwent ViV-OS (54% vs 3%, respectively; P < 0.001. There was no difference in mortality at 3 years between the 2 groups (P = 0.59). CONCLUSIONS: Patients who underwent ViV-IS had a very high incidence of coronary compromise that can be safely and effectively treated. In the setting of a systematic coronary protection strategy, ViV-OS and ViV-IS provide similar mid-term outcome, and periprocedural hemodynamic status (following adjustment for age, sex, and true internal diameter).

Sex differences in aortic stenosis: Identification of knowledge gaps for sex-specific personalized medicine.

Objectives: This review summarizes sex-based differences in aortic stenosis (AS) and identifies knowledge gaps that should be addressed by future studies. Background: AS is the most common valvular heart disease in developed countries. Sex-specific differences have not been fully appreciated, as a result of widespread under diagnosis of AS in women. Summary: Studies including sex-stratified analyses have shown differences in pathophysiology with less calcification and more fibrosis in women's aortic valve. Women have impaired myocardial perfusion reserve and different compensatory response of the left ventricle (LV) to pressure overload, with concentric remodeling and more diffuse fibrosis, in contrast to men with more focal fibrosis and more dilated/eccentrically remodeled LV. There is sex difference in clinical presentation and anatomical characteristics, with women having more paradoxical low-flow/low-gradient AS, under-diagnosis and severity underestimated, with less referral to aortic valve replacement (AVR) compared to men. The response to therapies is also different: women have more adverse events with surgical AVR and greater survival benefit with transcatheter AVR. After AVR, women would have more favorable LV remodeling, but sex-related differences in changes in myocardial reserve flow need future research. Conclusions: Investigation into these described sex-related differences in AS offers potential utility for improving prevention and treatment of AS in women and men. To better understand sex-based differences in pathophysiology, clinical presentation, and response to therapies, sex-specific critical knowledge gaps should be addressed in future research for sex-specific personalized medicine.

Left ventricular circumferential strain and coronary microvascular dysfunction: A report from the Women's Ischemia Syndrome Evaluation Coronary Vascular Dysfunction (WISE-CVD) Project.

AIMS: Women with ischemia but no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). Left ventricular (LV) circumferential strain (CS) is often lower in INOCA compared to healthy controls; however, it remains unclear whether CS differs between INOCA women with and without CMD. We hypothesized that CS would be lower in women with CMD, consistent with CMD-induced LV mechanical dysfunction. METHODS AND RESULTS: Cardiac magnetic resonance (cMR) images were examined from women enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction Project. CS by feature tracking in INOCA women with CMD, defined as myocardial perfusion reserve index (MPRI) <1.84 during adenosine-stress perfusion cMR, was compared with CS in women without CMD. In a subset who had invasive coronary function testing (CFT), the relationship between CS and CFT metrics, LV ejection fraction (LVEF) and cardiovascular risk factors was investigated. Among 317 women with INOCA, 174 (55%) had CMD measured by MPRI. CS was greater in women with CMD compared to those without CMD (23.2 ± 2.5% vs. 22.1 ± 3.0%, respectively, P = 0.001). In the subset with CFT (n = 153), greater CS was associated with increased likelihood of reduced vasodilator capacity (OR = 1.33, 95%CI = 1.02-1.72, p = 0.03) and discriminated abnormal vs. normal coronary vascular function compared to CAD risk factors, LVEF and LV concentricity (AUC: 0.82 [0.73-0.96 95%CI] vs. 0.65 [0.60-0.71 95%CI], respectively, P = 0.007). CONCLUSION: The data indicate that LV circumferential strain is related to and predicts CMD, although in a direction contrary with our hypothesis, which may represent an early sign of LV mechanical dysfunction in CMD.

Coronary Vascular Function and Cardiomyocyte Injury: A Report From the WISE-CVD.

OBJECTIVE: Women with symptoms or signs of myocardial ischemia but no obstructive coronary artery disease (INOCA) often have coronary vascular dysfunction and elevated risk for adverse cardiovascular events. We hypothesized that u-hscTnI (ultra-high-sensitivity cardiac troponin I), a sensitive indicator of ischemic cardiomyocyte injury, is associated with coronary vascular dysfunction in women with INOCA. Approach and Results: Women (N=263) with INOCA enrolled in the WISE-CVD study (Women's Ischemic Syndrome Evaluation-Coronary Vascular Dysfunction) underwent invasive coronary vascular function testing and u-hscTnI measurements (Simoa HD-1 Analyzer; Quanterix Corporation, Lexington, MA). Logistic regression models, adjusted for traditional cardiovascular risk factors were used to evaluate associations between u-hscTnI and coronary vascular function. Women with coronary vascular dysfunction (microvascular constriction and limited coronary epicardial dilation) had higher plasma u-hscTnI levels (both P=0.001). u-hscTnI levels were associated with microvascular constriction (odds ratio, 1.38 per doubling of u-hscTnI [95% CI, 1.03-1.84]; P=0.033) and limited coronary epicardial dilation (odds ratio, 1.37 per doubling of u-hscTnI [95% CI, 1.04-1.81]; P=0.026). u-hscTnI levels were not associated with microvascular dilation or coronary epicardial constriction. CONCLUSIONS: Our findings indicate that higher u-hscTnI is associated with coronary vascular dysfunction in women with INOCA. This suggests that ischemic cardiomyocyte injury in the setting of coronary vascular dysfunction has the potential to contribute to adverse cardiovascular outcomes observed in these women. Additional studies are needed to confirm and investigate mechanisms underlying these findings in INOCA. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00832702.

Oxidative Stress Is Associated With Diastolic Dysfunction in Women With Ischemia With No Obstructive Coronary Artery Disease.

Background Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have evidence of diastolic dysfunction. Oxidative stress (OS) is associated with cardiovascular risk factors and adverse outcomes. The relationship between systemic OS and diastolic dysfunction is unknown. Methods and Results A subgroup of women (n=75) with suspected ischemia and no obstructive coronary artery disease who had both cardiac magnetic resonance imaging and OS measurements were enrolled in the WISE-CVD (Women Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction) study. Left ventricular end-diastolic pressure was measured invasively. Left ventricular end-diastolic volume and peak filling rate were assessed using cardiac magnetic resonance imaging. Aminothiol levels of plasma cystine and glutathione were measured as markers of OS. Spearman correlation and linear regression analyses were conducted. The group mean age was 54±11 years, and 61% had a resting left ventricular end-diastolic pressure >12 mm Hg. Cystine levels correlated negatively with the peak filling rate (r=-0.31, P=0.007) and positively with left ventricular end-diastolic pressure (r=0.25; P=0.038), indicating that increased OS was associated with diastolic dysfunction. After multivariate adjustment including multiple known risk factors for diastolic dysfunction and cardiovascular medications, cystine levels continued to be associated with peak filling rate (ß=-0.27, P=0.049) and left ventricular end-diastolic pressure (ß=0.25; P=0.035). Glutathione levels were not associated with indices of diastolic function. Conclusions OS, measured by elevated levels of cystine, is associated with diastolic dysfunction in women with evidence of ischemia and no obstructive coronary artery disease, indicating the role of OS in patients with ischemia and no obstructive coronary artery disease. Its role in the progression of heart failure with preserved ejection fraction should be explored further.

Rationale and design of the quantification of myocardial blood flow using dynamic PET/CTA-fused imagery (DEMYSTIFY) to determine physiological significance of specific coronary lesions.

BACKGROUND: Coronary physiology assessments have been shown by multiple trials to add clinical value in detecting significant coronary artery disease and predicting cardiovascular outcomes. Fractional flow reserve (FFR) obtained during invasive coronary angiography (ICA) has become the new reference standard for hemodynamic significance detection. Absolute myocardial blood flow (MBF) quantification by means of dynamic positron emission tomography (dPET) has high diagnostic and prognostic values. FFR is an invasive measure and as such cannot be applied broadly, while MBF quantification is commonly performed on standard vascular territories intermixing normal flow from normal regions with abnormal flow from abnormal regions and consequently limiting its diagnostic power. OBJECTIVE: The aim of this study is to provide physicians with reliable software tools for the non-invasive assessment of lesion-specific physiological significance for the entire coronary tree by combining PET-derived absolute flow data and coronary computed tomography angiography (CTA)-derived anatomy and coronary centerlines. METHODS: The dynamic PET/CTA myocardial blood flow assessment with fused imagery (DEMYSTIFY) study is an observational prospective clinical study to develop algorithms and software tools to fuse coronary anatomy data obtained from CTA with dPET data to non-invasively measure absolute MBF, myocardial flow reserve, and relative flow reserve across specific coronary lesions. Patients (N = 108) will be collected from 4 institutions (Emory University Hospital, USA; Chonnam National University Hospital, South Korea; Samsung Medical Center, South Korea; Seoul National University Hospital, South Korea). These results will be compared to those obtained invasively in the catheterization laboratory and to a relatively novel non-invasive technique to estimate FFR based on CTA and computational fluid dynamics. CONCLUSIONS: Success of these developments should lead to the following benefits: (1) eliminate unnecessary invasive coronary angiography in patients with no significant lesions, (2) avoid stenting physiologically insignificant lesions, (3) guide percutaneous coronary interventions process to the location of significant lesions, (4) provide a flow-color-coded 3D roadmap of the entire coronary tree to guide bypass surgery, and (5) use less radiation and lower the cost from unnecessary procedures. TRIAL REGISTRY: The DEMYSTIFY study has been registered on ClinicalTrials.gov with registration number NCT04221594.

Myocardial Infarction and Persistent Angina With No Obstructive Coronary Artery Disease.

Women with myocardial infarction with no obstructive coronary artery disease (MINOCA) are increasingly recognized. Women with MINOCA are at high risk for major adverse cardiovascular events. In this case, we focus on the importance of early identification and management of MINOCA to improve patients' angina and related quality of life. (Level of Difficulty: Beginner.).

Design, methodology and baseline characteristics of the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD).

A significant number of women with signs and symptoms of ischemia with no obstructive coronary artery disease (INOCA) have coronary vascular dysfunction detected by invasive coronary reactivity testing (CRT). However, the noninvasive assessment of coronary vascular dysfunction has been limited. METHODS: The Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) was a prospective study of women with suspected INOCA aimed to investigate whether (1) cardiac magnetic resonance imaging (CMRI) abnormalities in left ventricular morphology and function and myocardial perfusion predict CRT measured coronary microvascular dysfunction, (2) these persistent CMRI abnormalities at 1-year follow-up predict persistent symptoms of ischemia, and (3) these CMRI abnormalities predict cardiovascular outcomes. By design, a sample size of 375 women undergoing clinically indicated invasive coronary angiography for suspected INOCA was projected to complete baseline CMRI, a priori subgroup of 200 clinically indicated CRTs, and a priori subgroup of 200 repeat 1-year follow-up CMRIs. RESULTS: A total of 437 women enrolled between 2008 and 2015, 374 completed baseline CMRI, 279 completed CRT, and 214 completed 1-year follow-up CMRI. Mean age was 55±â€¯11 years, 93% had 20%-50% coronary stenosis, and 7% had <20% stenosis by angiography. CONCLUSIONS: The WISE-CVD study investigates the utility of noninvasive CMRI to predict coronary vascular dysfunction in comparison to invasive CRT, and the prognostic value of CMRI abnormalities for persistent symptoms of ischemia and cardiovascular outcomes in women with INOCA. WISE-CVD will provide new understanding of a noninvasive imaging modality for future clinical trials.

The role of coronary reactivity testing in women with no obstructive coronary artery disease.

PURPOSE OF REVIEW: Two-thirds of women with signs and symptoms of ischemia and no obstructive coronary artery disease (INOCA) have abnormal coronary reactivity. These women are challenging to assess, diagnose and manage because of a lack of evidence-based guidelines. Furthermore, they are considered to be at 'low risk' by most physicians, often receive no specific therapy and tend to be dismissed from subspecialty care. RECENT FINDINGS: Coronary reactivity testing (CRT) is considered the reference-standard for evaluation of epicardial and microvascular coronary function in response to various vasoactive agents. It provides a comprehensive vascular function assessment for diagnosis, a guide for management, and has prognostic benefit that outweighs the risk of the procedure. We recently demonstrated the prognostic value of assessing coronary vascular reactivity in women with signs and symptoms of ischemia, especially those with no obstructive coronary artery disease. SUMMARY: Invasive CRT is a feasible, useful method to identify coronary microvascular dysfunction (CMD) and risk stratify women with INOCA. It has a comparable safety record with other invasive procedures. Future research is directed at optimizing patient selection, streamlining of invasive CRT methods using user-friendly catheters to enhance feasibility in the routine clinical setting, and optimizing treatment protocols, with clinical trials designed to evaluate outcomes.

Impact of Abnormal Coronary Reactivity on Long-Term Clinical Outcomes in Women.

BACKGROUND: Currently as many as one-half of women with suspected myocardial ischemia have no obstructive coronary artery disease (CAD), and abnormal coronary reactivity (CR) is commonly found. OBJECTIVES: The authors prospectively investigated CR and longer-term adverse cardiovascular outcomes in women with and with no obstructive CAD in the National Heart, Lung, and Blood Institute-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. METHODS: Women (n = 224) with signs and symptoms of ischemia underwent CR testing. Coronary flow reserve and coronary blood flow were obtained to test microvascular function, whereas epicardial CR was tested by coronary dilation response to intracoronary (IC) acetylcholine and IC nitroglycerin. All-cause mortality, major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, stroke, and heart failure), and angina hospitalizations served as clinical outcomes over a median follow-up of 9.7 years. RESULTS: The authors identified 129 events during the follow-up period. Low coronary flow reserve was a predictor of increased MACE rate (hazard ratio [HR]: 1.06; 95% confidence interval [CI]: 1.01 to 1.12; p = 0.021), whereas low coronary blood flow was associated with increased risk of mortality (HR: 1.12; 95% CI: 1.01 to 1.24; p = 0.038) and MACE (HR: 1.11; 95% CI: 1.03 to 1.20; p = 0.006) after adjusting for cardiovascular risk factors. In addition, a decrease in cross-sectional area in response to IC acetylcholine was associated with higher hazard of angina hospitalization (HR: 1.05; 95% CI: 1.02 to 1.07; p < 0.0001). There was no association between epicardial IC-nitroglycerin dilation and outcomes. CONCLUSIONS: On longer-term follow-up, impaired microvascular function predicts adverse cardiovascular outcomes in women with signs and symptoms of ischemia. Evaluation of CR abnormality can identify those at higher risk of adverse outcomes in the absence of significant CAD. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00000554).

Typical angina is associated with greater coronary endothelial dysfunction but not abnormal vasodilatory reserve.

BACKGROUND: Typical angina (TA) is defined as substernal chest pain precipitated by physical exertion or emotional stress and relieved with rest or nitroglycerin. Women and elderly patients are usually have atypical symptoms both at rest and during stress, often in the setting of nonobstructive coronary artery disease (CAD). HYPOTHESIS: To further understand this, we performed subgroup analysis comparing subjects who presented with TA vs nontypical angina (NTA) using baseline data of patients with nonobstructive CAD and coronary microvascular dysfunction (CMD) enrolled in a clinical trial. METHODS: 155 subjects from the RWISE study were divided into 2 groups based on angina characteristics: TA (defined as above) and NTA (angina that does not meet criteria for TA). Coronary reactivity testing (responses to adenosine, acetylcholine, and nitroglycerin), cardiac magnetic resonance-determined myocardial perfusion reserve index (MPRI), baseline Seattle Angina Questionnaire (SAQ), and Duke Activity Status Index (DASI) scores were evaluated. RESULTS: The mean age was 55 ± 10 years; Overall, 30% of subjects had TA. Baseline shortness of breath, invasively assessed acetylcholine-mediated coronary endothelial function, and SAQ score were worse in the TA group (all P < 0.05), whereas adenosine-mediated coronary flow reserve, MPRI, and DASI score were similar to the NTA group. CONCLUSIONS: Among subjects with CMD and no obstructive CAD, those with TA had more angina pectoris, shortness of breath, and worse quality of life, as well as more severe coronary endothelial dysfunction. Typical angina in the setting of CMD is associated with worse symptom burden and coronary endothelial dysfunction. These results indicate that TA CMD subjects represent a relatively new CAD phenotype for future study and treatment trials.

Inflammatory biomarkers as predictors of heart failure in women without obstructive coronary artery disease: A report from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: Women with signs and symptoms of ischemia, no obstructive coronary artery disease (CAD) and preserved left ventricular ejection fraction (EF) often have diastolic dysfunction and experience elevated rates of major adverse cardiac events (MACE), including heart failure (HF) hospitalization with preserved ejection fraction (HFpEF). We evaluated the predictive value of inflammatory biomarkers for long-term HF hospitalization and all-cause mortality in these women. METHODS: We performed a cross-sectional analysis to investigate the relationships between inflammatory biomarkers [serum interleukin-6 (IL-6), C-reactive protein (hs-CRP) and serum amyloid A (SAA)] and median of 6 years follow-up for all-cause mortality and HF hospitalization among women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF. Multivariable Cox regression analysis tested associations between biomarker levels and adverse outcomes. RESULTS: Among 390 women, mean age 56 ± 11 years, median follow up of 6 years, we observed that there is continuous association between IL-6 level and HF hospitalization (adjusted hazard ratio [AHR] 2.5 [1.2-5.0], p = 0.02). In addition, we found significant association between IL-6, SAA levels and all-cause mortality AHR (1.8 [1.1-3.0], p = 0.01) (1.5 [1.0-2.1], p = 0.04), respectively. CONCLUSION: In women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF, elevated IL-6 predicted HF hospitalization and all-cause mortality, while SAA level was only associated with all-cause mortality. These results suggest that inflammation plays a role in the pathogenesis of development of HFpEF, as well all-cause mortality.

Acetylcholine versus cold pressor testing for evaluation of coronary endothelial function.

BACKGROUND: Assessment of coronary endothelial function with intracoronary acetylcholine (IC-Ach) provides diagnostic and prognostic data in patients with suspected coronary microvascular dysfunction (CMD), but is often not feasible due in part to the time and expertise needed for pharmacologic mixing. Cold pressor testing (CPT) is a simple and safe stimulus useful for either invasive or non-invasive endothelial function testing and myocardial perfusion imaging but has not been specifically evaluated among symptomatic women with signs of ischemic heart disease (IHD) who have no obstructive coronary artery disease (CAD). METHODS: 163 women with signs and symptoms of IHD and no obstructive CAD from the NHLBI- Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study underwent coronary reactivity testing with a Doppler flow wire (FloWire® Volcano, San Diego, CA) in the proximal left anterior descending artery. Coronary artery diameter and coronary blood flow (CBF) assessed by core lab using QCA before and after IC-Ach (18.2 µg/ml infused over 3 minutes) and during CPT. RESULTS: Mean age was 55 ± 12 years. Rate pressure product (RPP) in response to IC-Ach did not change (baseline to peak, P = 0.26), but increased during CPT (363±1457; P = 0.0028). CBF in response to CPT was poorly correlated to IC-Ach CBF. Change in coronary artery diameter after IC-Ach correlated with change after CPT (r = 0.59, P<0.001). The correlation coefficient was stronger in subjects with coronary dilation to IC-Ach (r = 0.628, P<0.001) versus those without dilation (r = 0.353, P = 0.002), suggesting that other factors may be important to this relationship when endothelium is abnormal. CONCLUSIONS: In women with no obstructive CAD and suspected CMD, coronary diameter changes with IC-Ach and CPT are moderately-well correlated suggesting that CPT testing may be of some use, particularly among patients with normal endothelial function, however, not an alternative to IC-Ach for diagnosis of coronary endothelial dysfunction.

Cold Pressor Stress Cardiac Magnetic Resonance Myocardial Flow Reserve Is Not Useful for Detection of Coronary Endothelial Dysfunction in Women with Signs and Symptoms of Ischemia and No Obstructive CAD.

BACKGROUND: Coronary endothelial function testing using acetylcholine is not routinely available, while non-pharmacological cold pressor testing (CPT) is considered an endothelial stressor. Noninvasive cardiac magnetic resonance imaging (CMRI) myocardial perfusion reserve index (MPRI) can detect coronary microvascular dysfunction (CMD). We evaluated if CPT stress CMRI MPRI could detect invasive coronary endothelial dysfunction. METHODS: Coronary reactivity testing was performed in 189 women with symptoms and signs of ischemic but no obstructive coronary artery disease as previously described plus CPT stress. Subjects also underwent pharmacologic and CPT stress during CMRI (1.5 T). Statistical analysis comparing CPT MPRI between groups was performed by Welch`s t-test and Mann-Whitney where appropriate. Anderson-Darling test and Levene test were considered to verify the normality and homogeneity of variances assumptions. Correlation analyses between CPT MPRI and both invasive and noninvasive measures of CMD were performed using Spearman correlation. RESULTS: While CPT MPRI correlated with pharmacological stress MPRI, it did not correlate with invasive measures of CMD including invasively measured responses to intracoronary (IC) adenosine, IC acetylcholine, CPT, or IC nitroglycerin. Additionally CPT MPRI was not significantly different between subjects with normal compared to abnormal pharm stress MPRI or normal compared to abnormal invasive CMD parameters. CONCLUSION: Despite correlation with pharmacological stress MPRI, non-invasive CPT MPRI does not appear to be useful for detecting CMD in symptomatic women.

Coronary Microvascular Dysfunction　- Epidemiology, Pathogenesis, Prognosis, Diagnosis, Risk Factors and Therapy.

Angina has traditionally been thought to be caused by obstructive coronary artery disease (CAD). However, a substantial number of patients with angina are found to not have obstructive CAD when undergoing coronary angiography. A significant proportion of these patients have coronary microvascular dysfunction (CMD), characterized by heightened sensitivity to vasoconstrictor stimuli and limited microvascular vasodilator capacity. With the advent of non-invasive and invasive techniques, the coronary microvasculature has been more extensively studied in the past 2 decades. CMD has been identified as a cause of cardiac ischemia, in addition to traditional atherosclerotic disease and vasospastic disease. CMD can occur alone or in the presence obstructive CAD. CMD shares many similar risk factors with macrovascular CAD. Diagnosis is achieved through detection of an attenuated response of coronary blood flow in response to vasodilatory agents. Imaging modalities such as cardiovascular magnetic resonance, positron emission tomography, and transthoracic Doppler echocardiography have become more widely used, but have not yet completely replaced the traditional intracoronary vasoreactivity testing. Treatment of CMD starts with lifestyle modification and risk factor control. The use of traditional antianginal, antiatherosclerotic medications and some novel agents may be beneficial; however, clinical trials are needed to assess the efficacy of the pharmacologic and non-pharmacologic therapeutic modalities. In addition, studies with longer-term follow-up are needed to determine the prognostic benefits of these agents. We review the epidemiology, prognosis, pathogenesis, diagnosis, risk factors and current therapies for CMD.