Case report: Repeat coronary function testing in women with ischemia and no obstructive coronary artery disease.

Women with signs and symptoms of ischemia and no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). It can be diagnosed by coronary function testing (CFT), which is an invasive coronary angiogram procedure. Frequently, these women have persistent angina despite medical therapy, but it is not clear whether it is due to worsening or persistent CMD or inadequate therapy. In this brief report, we describe findings of repeat CFT in a case series of 12 women undergoing repeat CFT for the assessment of persistent angina in order to better understand the evolving pathology.

Left ventricular ejection fraction and long-term outcomes in women presenting with signs and symptoms of ischaemia.

BACKGROUND: Although women are known to have a relatively higher left ventricular ejection fraction (LVEF) compared with men, a sex-neutral LVEF threshold continues to be used for clinical management. We sought to investigate the relationship among high (>65%), normal (55%-65%) and low (<55%) LVEF and long-term all-cause mortality and major adverse cardiovascular events (MACEs) in women presenting with suspected myocardial ischaemia. METHODS: A total of 734 women from the Women's Ischemia Syndrome Evaluation (WISE) were analysed. LVEF was calculated by invasive left ventriculography. The relationship between baseline characteristics, LVEF and outcomes was evaluated. A multivariable Cox regression model was used to assess the association of LVEF with outcomes, after adjusting for known risk factors. RESULTS: Low LVEF was associated with higher rates of mortality and MACE compared with normal and high LVEF (p<0.0001). Normal LVEF was associated with higher mortality (p=0.047) and rate of myocardial infarctions (MIs) compared with high LVEF (p=0.03). Low LVEF remained a significant predictor of mortality compared with high LVEF (p=0.013) in a multivariable regression model and normal compared with high LVEF trended towards higher mortality (p=0.16). CONCLUSION: Among women with suspected ischaemia, women with LVEF above the defined normal threshold (>65%) had lower rates of all-cause mortality and non-fatal MI. Further investigation is needed to determine the optimal LVEF in women. TRIAL REGISTRATION NUMBER: NCT00000554.

Fitness attenuates long-term cardiovascular outcomes in women with ischemic heart disease and metabolic syndrome.

Background: The prevalence of metabolic syndrome continues to increase steadily while fitness remains relatively low. The contribution of fitness on longer-term cardiovascular outcomes and mortality in individuals with cardiovascular disease and metabolic syndrome remains unknown. Design: Women's Ischemia Syndrome Evaluation (WISE) prospective cohort (enrolled 1996-2001) of women undergoing invasive coronary angiography with signs/symptoms of ischemic heart disease. Methods: Investigated the association of fitness, defined as >7METs measured by self-reported Duke Activity Status Index (DASI), and both metabolic syndrome (ATPIII criteria) and dysmetabolism (ATPIII criteria and/or treated diabetes) with long-term cardiovascular outcomes and all-cause mortality risk. Results: Among the 492 women followed for a median of 8.6 years (range 0-11 years), 19.5% were fit-metabolically healthy (reference), 14.4% fit-metabolic syndrome, 29.9% unfit-metabolically healthy, and 36.2% unfit-metabolic syndrome. Compared to reference, MACE risk was 1.52-fold higher in fit-metabolic syndrome women (HR 1.52, 95% CI 1.03-2.26) and 2.42-fold higher in unfit-metabolic syndrome women (HR 2.42, 95% CI 1.30-4.48). Compared to reference, mortality risk was 1.96-fold higher in fit-dysmetabolism (HR 1.96, 95% CI 1.29-3.00) and 3-fold higher in unfit-dysmetabolism women (HR 3.0, 95% CI 1.66-5.43). Conclusions: In a high risk cohort of women with signs/symptoms of ischemic heart disease, unfit-metabolically healthy and fit-metabolically unhealthy women were at higher risk of long-term MACE and mortality compared to fit-metabolically healthy women; and women who were unfit and metabolically unhealthy were at the highest risk. Our study demonstrates that metabolic health and fitness play an important role in long term outcomes that warrants further investigation. Registration: https://www.clinicaltrials.gov/ct2/show/NCT00000554 (NCT00000554).

Ultra-high sensitivity cardiac troponin-I concentration and left ventricular structure and function in women with ischemia and no obstructive coronary artery disease.

Aims: Women are disproportionally impacted by ischemia and no obstructive coronary artery disease (INOCA), and such women are at increased risk of developing heart failure with preserved ejection fraction (HFpEF), however the mechanisms linking these conditions remain poorly understood. The aim of this study was to determine whether ultra-high sensitivity cardiac troponin I (u-hscTnI), an indicator of cardiomyocyte injury, is associated with abnormalities in myocardial perfusion and left ventricular (LV) structure and function in women with INOCA. Methods: 327 women with INOCA enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study underwent vasodilator stress cardiac magnetic resonance imaging (CMRI) and u-hscTnI measurements (Simoa HD-1 Analyzer, Quanterix Corporation). Multivariable linear regression was used to evaluate associations between u-hscTnI concentrations and myocardial perfusion (MPRI), LV mass index and feature-tracking derived strain measures of LV function. Results: u-hscTnI concentrations were quantifiable in 100% of the cohort and ranged from 0.004 to 79.6 pg/mL. In adjusted models, u-hscTnI was associated with LV mass index (+2.03; 95% CI 1.17, 2.89; p < 0.01) and early diastolic radial strain rate (SR) (+0.13; 95% CI 0.01, 0.25; p = 0.03), early diastolic circumferential SR (-0.04; 95% CI -0.08, 0.002; p = 0.06) and early diastolic longitudinal SR (-0.03; 95% CI -0.07, 0.002; p = 0.06). u-hscTnI was not associated with MPRI (p = 0.39) in adjusted models. Conclusion: Together, these findings support cardiomyocyte injury as a putative pathway towards adverse LV remodeling and dysfunction; however, further research is needed to define the specific mechanism(s) driving myocellular injury in INOCA.

Reduced myocardial perfusion is common among subjects with ischemia and no obstructive coronary artery disease and heart failure with preserved ejection fraction: a report from the WISE-CVD continuation study.

Aim: Women with evidence of ischemia and no obstructive coronary artery disease (INOCA) have an increased risk of major adverse cardiac events, including heart failure with preserved ejection fraction (HFpEF). To investigate potential links between INOCA and HFpEF, we examined pathophysiological findings present in both INOCA and HFpEF. Methods: We performed adenosine stress cardiac magnetic resonance imaging (CMRI) in 56 participants, including 35 women with suspected INOCA, 13 women with HFpEF, and 8 reference control women. Myocardial perfusion imaging was performed at rest and with vasodilator stress with intravenous adenosine. Myocardial perfusion reserve index was quantified as the ratio of the upslope of increase in myocardial contrast at stress vs. rest. All CMRI measures were quantified using CVI42 software (Circle Cardiovascular Imaging Inc). Statistical analysis was performed using linear regression models, Fisher's exact tests, ANOVA, or Kruskal-Wallis tests. Results: Age (P = 0.007), Body surface area (0.05) were higher in the HFpEF group. Left ventricular ejection fraction (P = 0.02) was lower among the INOCA and HFpEF groups than reference controls after age adjustment. In addition, there was a graded reduction in myocardial perfusion reserve index in HFpEF vs. INOCA vs. reference controls (1.5 ± 0.3, 1.8 ± 0.3, 1.9 ± 0.3, P = 0.02), which was attenuated with age-adjustment. Conclusion: Reduced myocardial perfusion reserve appears to be a common pathophysiologic feature in INOCA and HFpEF patients.

Body weight and physical fitness in women with ischaemic heart disease: does physical fitness contribute to our understanding of the obesity paradox in women?

AIMS: Body mass index (BMI) defined obesity is paradoxically associated with lower all-cause mortality in patients with known cardiovascular disease. This study aims to determine the role of physical fitness in the obesity paradox in women with ischaemic heart disease (IHD). METHODS AND RESULTS: Women undergoing invasive coronary angiography with signs/symptoms of IHD in the Women's Ischemia Syndrome Evaluation (WISE) prospective cohort (enrolled 1997-2001) were analysed. This study investigated the longer-term risk of major adverse cardiovascular events (MACE) and all-cause mortality associated with BMI and physical fitness measured by Duke Activity Status Index (DASI). Overweight was defined as BMl ≥25 to 30 kg/m2, obese as BMI ≥30 kg/m2, unfit as DASI scores <25, equivalent to ≤7 metabolic equivalents. Among 899 women, 18.6% were normal BMI-fit, 11.4% overweight-fit, 10.4% obese-fit, 15.3% normal BMI-unfit, 23.8% overweight-unfit, and 30.4% obese-unfit. In adjusted models compared to normal BMI-fit, normal BMI-unfit women had higher MACE risk [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.17-2.32; P = 0.004]; whereas obese-fit and overweight-fit women had lower risk of mortality (HR 0.60, 95% CI 0.40-0.89; P = 0.012 and HR 0.62, 95% CI 0.41-0.92; P = 0.018, respectively). CONCLUSION: To address the paradox of body weight and outcomes in women, we report for the first time that among women with signs/symptoms of IHD overweight-fit and obese-fit were at lower risk of long-term all-cause mortality; whereas normal BMI-unfit were at higher risk of MACE. Physical fitness may contribute to the obesity paradox in women, warranting future studies to better understand associations between body weight, body composition, and physical fitness to improve cardiovascular outcomes in women.

Angina relates to coronary flow in women with ischemia and no obstructive coronary artery disease.

BACKGROUND: Women with suspected ischemia and no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD) as measured by impaired coronary flow reserve (CFR), which is associated with angina and adverse cardiovascular events. CFR is a ratio of hyperemic to baseline average peak velocity (bAPV), and the relation of baseline flow to angina is not understood. METHODS: We evaluated 259 women enrolled in the WISE-Coronary Vascular Dysfunction (WISE-CVD) project with suspected CMD who underwent invasive coronary functional testing. We analyzed variables stratified by high (e.g. ≥22 cm/s) vs low (<22 cm/s) bAPV, using t-test or Wilcoxon rank; linear and multivariable regression was used with bAPV as a continuous variable. RESULTS: Women with high bAPV had worse Seattle Angina Questionnaire (SAQ) angina frequency (58 ± 26 vs 67 ± 25, p = 0.005) and SAQ-7 scores (57 ± 22 vs 62 ± 21, p = 0.03), with higher nitrate (p = 0.02) and ranolazine use (p = 0.03). The high bAPV subgroup also had lower CFR (p < 0.001)). Linear regression related higher bAPV with lower SAQ-7 (p = 0.01) and lower angina frequency scores (p = 0.001). These results remained significant in multivariable modelling adjusting for baseline differences (p < 0.04). SAQ-7 was significantly predicted by bAPV. CONCLUSIONS: Among women with suspected INOCA, angina relates to high bAPV, a result supported by the concomitant greater use of anti-anginal drugs. These results suggest that high bAPV contributes to impaired CFR and may represent a specific pathophysiologic contributor to CMD and may be a treatment target in INOCA subjects.

Diastolic dysfunction in women with ischemia and no obstructive coronary artery disease: Mechanistic insight from magnetic resonance imaging.

BACKGROUND: Ischemia with no obstructive coronary artery disease (INOCA) is prevalent in women and is associated with increased risk of developing heart failure with preserved ejection fraction (HFpEF); however, the mechanism(s) contributing to this progression remains unclear. Given that diastolic dysfunction is common in women with INOCA, defining mechanisms related to diastolic dysfunction in INOCA could identify therapeutic targets to prevent HFpEF. METHODS: Cardiac MRI was performed in 65 women with INOCA and 12 reference controls. Diastolic function was defined by left ventricular early diastolic circumferential strain rate (eCSRd). Contributors to diastolic dysfunction were chosen a priori as coronary vascular dysfunction (myocardial perfusion reserve index [MPRI]), diffuse myocardial fibrosis (extracellular volume [ECV]), and aortic stiffness (aortic pulse wave velocity [aPWV]). RESULTS: Compared to controls, eCSRd was lower in INOCA (1.61 ± 0.33/s vs. 1.36 ± 0.31/s, P = 0.016); however, this difference was not exaggerated when the INOCA group was sub-divided by low and high MPRI (P > 0.05) nor was ECV elevated in INOCA (29.0 ± 1.9% vs. 28.0 ± 3.2%, control vs. INOCA; P = 0.38). However, aPWV was higher in INOCA vs. controls (8.1 ± 3.2 m/s vs. 6.1 ± 1.5 m/s; P = 0.045), and was associated with eCSRd (r = -0.50, P < 0.001). By multivariable linear regression analysis, aPWV was an independent predictor of decreased eCSRd (standardized ß = -0.39, P = 0.003), as was having an elevated left ventricular mass index (standardized ß = -0.25, P = 0.024) and lower ECV (standardized ß = 0.30, P = 0.003). CONCLUSIONS: These data provide mechanistic insight into diastolic dysfunction in women with INOCA, identifying aortic stiffness and ventricular remodeling as putative therapeutic targets.

The Masquerading, Masculinizing Tumor: A Case Report and Review of the Literature.

Androgen-producing tumors in women are rare neoplasms that can cause secondary virilizing characteristics. Of patients presenting with symptoms of hyperandrogenism, these tumors are found in ∼0.2% of cases. Androgen-producing tumors can arise from the ovary or the adrenal gland. Those arising from the ovary are rare, accounting for <5% of all ovarian tumors. This case presents a hilar Leydig cell tumor of the ovary, which resulted in secondary virilization of a 45-year-old female 2 months after cessation of combined oral contraceptives (COC). Laboratory findings showed markedly elevated total and free testosterone concentrations with normal dehydroepiandrosterone sulfate, however neither pelvic ultrasound nor magnetic resonance imaging demonstrated any masses. Venous sampling under fluoroscopy revealed supraphysiologic testosterone concentrations from the right ovarian vein suggesting the source. The patient underwent bilateral salpingo-oophorectomy revealing a 1.3 cm hilar cell tumor of the right ovary. This article reviews the clinical features, diagnosis, and treatment of hilar Leydig cell tumors and describes the long-term complications of supraphysiologic testosterone levels. As the tumor presented after cessation of COC, we also review the mechanisms by which COC might suppress supraphysiologic androgen levels and mask the secondary virilizing effects of androgen-producing tumors.

Temporal Trends in Angina, Myocardial Perfusion, and Left Ventricular Remodeling in Women With No Obstructive Coronary Artery Disease Over 1-Year Follow-Up: Results From WISE-CVD.

Background Women with ischemia and no obstructive coronary artery disease are increasingly recognized and found to be at risk for major adverse cardiovascular events. Methods and Results In 214 women with suspected ischemia and no obstructive coronary artery disease who completed baseline and 1-year follow-up vasodilatory stress cardiac magnetic resonance imaging, we investigated temporal trends in angina (Seattle Angina Questionnaire [SAQ]), myocardial perfusion reserve index, blood pressure, and left ventricular (LV) remodeling and function from baseline to 1-year follow-up and explored associations between these different parameters. We observed concordant positive trends in 4/5 SAQ domains, SAQ-7, myocardial perfusion reserve index, blood pressure, LV mass, and LV mass-to-volume ratio. There was no association between SAQ-7 improvement and myocardial perfusion reserve index improvement over 1-year follow-up (P=0.1). Higher indexed LV end-diastolic volume and time to peak filling rate at baseline were associated with increased odds of clinically relevant SAQ-7 improvement (odds ratio [OR], 1.05; 95% CI, 1.0-1.1; and OR, 2.40; 95% CI, 1.1-5.0, respectively). Hypertension was associated with decreased odds of SAQ-7 improvement (OR, 0.41; 95% CI, 0.19-0.91). Conclusions In women with ischemia and no obstructive coronary artery disease clinically treated with cardiac medications over 1 year, we observed concurrent temporal trends toward improvement in SAQ, myocardial perfusion reserve index, blood pressure, LV mass, and LV mass-to volume ratio. We showed that abnormalities in LV morphology and diastolic function at baseline were predictive of clinically significant improvement in angina at follow-up, whereas history of hypertension was associated with lower odds. Future studies are needed to assess the mechanisms and treatments responsible for the improvements we observed. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02582021.