Even "WISE-R?"-an Update on the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation.

PURPOSE OF REVIEW: For over 20 years, the Women's Ischemia Syndrome Evaluation (WISE), a program sponsored by the National Heart, Lung, and Blood Institute, has explored diverse and important aspects of ischemic heart disease in women. RECENT FINDINGS: Women with symptoms and signs of ischemia but no significant epicardial obstructive coronary artery disease (INOCA) were documented to be at elevated risk for recurrent angina hospitalization, major adverse cardiac events, death, and health resource consumption rivaling those with obstructive coronary disease. WISE investigators have advanced our understanding of cardiovascular outcomes, systemic manifestations, psychological variables, socioeconomic factors, genetic contributions, hormonal status, advanced imaging, coronary functional findings, biomarkers, patient-reported outcomes, and treatments pertaining to women with this disease entity. This review delves into the WISE findings subsequent to a prior review1, postulates directions for future research, and asks are we "Even 'WISE-R?'".

Sex-based differences in remote monitoring of biometric, psychometric and biomarker indices in stable ischemic heart disease.

BACKGROUND: Sex-based differences are crucial to consider in the formulation of a personalized treatment plan. We evaluated sex-based differences in adherence and remotely monitored biometric, psychometric, and biomarker data among patients with stable ischemic heart disease (IHD). METHODS: The Prediction, Risk, and Evaluation of Major Adverse Cardiac Events (PRE-MACE) study evaluated patients with stable IHD over a 12-week period. We collected biometric and sleep data using remote patient monitoring via FitBit and psychometric data from Patient-Reported Outcomes Measurement Information System (PROMIS), Kansas City Cardiomyopathy (KCC) and Seattle Angina Questionnaire-7 (SAQ-7) questionnaires. Serum biomarker levels were collected at the baseline visit. We explored sex-based differences in demographics, adherence to study protocols, biometric data, sleep, psychometric data, and biomarker levels. RESULTS: There were 198 patients enrolled, with mean age 65.5 ± 11 years (± Standard deviation, SD), and 60% were females. Females were less adherent to weekly collection of PROMIS, KCC and SAQ-7 physical limitations questionnaires (all p < 0.05), compared to males. There was no difference in biometric physical activity. There was a statistically significant (p < 0.05) difference in sleep duration between sexes, with females sleeping 6 min longer. However, females reported higher PROMIS sleep disturbance scores (p < 0.001) and poorer psychometric scores overall (p < 0.05). A higher proportion of males had clinically significant elevations of median N-terminal pro-brain natriuretic peptide (p = 0.005) and high-sensitivity cardiac troponin levels (p < 0.001) compared to females. CONCLUSIONS: Among females and males with stable IHD, there are sex-based differences in remote monitoring behavior and data. Females are less adherent to psychometric data collection and report poorer psychometric and sleep quality scores than males. Elevated levels of biomarkers for MACE are more common in males. These findings may improve sex-specific understanding of IHD using remote patient monitoring.

Coronary microvascular dysfunction: Considerations for diagnosis and treatment.

Ischemia and no obstructive coronary artery disease (INOCA) is an increasingly recognized cause of angina, and it is more commonly diagnosed in women. Coronary microvascular dysfunction (CMD), or the abnormal dilation and constriction of the small vessels of the heart, is the underlying cause of INOCA in one-half of cases. This review discusses coronary microvascular pathophysiology, considerations for invasive coronary function testing and noninvasive diagnostic modalities, implications for management, and remaining knowledge gaps.

Phytoestrogen blood levels and adverse outcomes in women with suspected ischemic heart disease.

BACKGROUND/OBJECTIVES: Prior studies linked higher blood phytoestrogen (phytoE) levels of daidzein to beneficial lipoprotein profiles, and higher genistein levels related to worse coronary microvascular dysfunction in women with suspected ischemic heart disease (IHD). However, relationships to adverse outcomes remain unclear. We investigated the associations between eight serum phytoE and major adverse cardiac events (MACE) including myocardial infarction, stroke, hospitalization for heart failure and angina, cardiovascular and all-cause mortality, in women undergoing functional coronary angiography (FCA) for suspected ischemia. SUBJECTS/METHODS: We evaluated 143 women enrolled in the Women's Ischemia Syndrome Evaluation (1996-2001) for serum phytoE levels and 10-year outcomes. Median follow-up duration was 6.08 years (range 0.01-8.16) for time to MACE and 9.11 years (range 0.01-11.08 years) for time to death. Kaplan-Meier plots were analyzed and Cox regression models adjusted for age, body mass index, hypertension, diabetes, dyslipidemia and tobacco use. RESULTS: The median age was 54.7 (range 20.6-76.1) years and BMI was 29.3 (range 18.4-57.2). Of the cohort, 80.4% had nonobstructive coronary artery disease, 56% had hypertension, 22.4% had diabetes, 58.1% had dyslipidemia and 59.4% of the women used tobacco. Each unit decrease in log glycitin was associated with increased MACE hazard (HR 1.97, 95% [CI 1.23, 3.14], p = 0.005). Glycitin absence was associated with earlier angina hospitalization (log rank p = 0.05). After 6 years, MACE increased with each unit decrease in log genistein (HR 6.17, 95% [CI 1.81, 20.8], p = 0.0036). Other phytoE did not show statistically significant associations with outcomes. CONCLUSIONS: Among women with suspected IHD undergoing clinically indicated invasive FCA, low serum glycitin was associated with increased MACE and earlier angina hospitalization, while low genistein was associated with increased MACE after 6 years. Future studies are needed regarding phytoE, nutrition, outcomes and possibly supplementation.

Prior Oral Contraceptive Use and Longer Term Mortality Outcomes in Women with Suspected Ischemic Heart Disease.

Background: Previous Women's Ischemia Syndrome Evaluation (WISE) work demonstrated prior oral contraceptive (OC) use was associated with lower coronary artery disease (CAD) in women with suspected ischemia. The association of prior OC use with longer term all-cause and cardiovascular disease (CVD) mortality is unclear. Materials and Methods: WISE women undergoing coronary angiography for suspected ischemia (enrolled 1996-2001) with prior OC use history and 10-year follow-up data were analyzed. A blinded core laboratory assessed atherosclerotic CAD severity. Kaplan-Meier analyses evaluated prior OC use relative to all-cause and CVD mortality. Cox regression analyses adjusted for baseline differences. Mediation, interaction, and multicollinearity were analyzed. Results: Our 686 women had a mean age 62.5 ± 9.6 years, multiple cardiac risk factors, and 39% previously used OC. Prior OC users were younger, with less lipid-lowering medication use and lower atherosclerotic CAD severity scores (all p < 0.05). Prior OC use was associated with lower 10-year all-cause (p = 0.007) and CVD mortality (p = 0.019). After adjustment, this was no longer significant (p = 0.77 and p = 0.90, respectively). Atherosclerotic CAD severity score mediated one-third of the observed association. Prior OC use was associated with increased CVD mortality among women with very elevated menopausal systolic blood pressure (SBP). Conclusions: Unadjusted prior OC use was associated with lower longer-term all-cause and CVD mortality. One-third of this observed effect appears mediated by the atherosclerotic CAD severity score. Prior OC was adversely associated with CVD mortality in women with very elevated menopausal SBP. Additional investigation is needed to understand the potential benefits and harms of prior OC use. Clinical Trial Number: NCT00000554, or https://www.clinicaltrials.gov/ct2/show/NCT00000554.

Biometric and Psychometric Remote Monitoring and Cardiovascular Risk Biomarkers in Ischemic Heart Disease.

Background Patients with stable ischemic heart disease represent a heterogeneous population at variable risk for major adverse cardiac events (MACE). Because MACE typically occurs outside the hospital, we studied whether biometric and psychometric remote patient monitoring are associated with MACE risk biomarkers. Methods and Results In 198 patients with stable ischemic heart disease (mean age 65±11 years, 60% women), we evaluated baseline measures, including biometric (FitBit 2) and psychometric (acquired via smartphone-administered patient-reported outcomes) remote monitoring, in the PRE-MACE (Prediction, Risk, and Evaluation of Major Adverse Cardiac Events) study. In multivariable adjusted regression analyses, we examined the association of these measures with biomarkers of MACE risk, including NT-proBNP (N-terminal pro-b-type natriuretic peptide), u-hs-cTnI (ultra-high sensitivity cardiac-specific troponin I), and hs-CRP (high-sensitivity C-reactive) protein. Both biometric and psychometric measures were associated with NT-proBNP. Specifically, step count, heart rate, physical activity, global health score, and physical function score were all inversely related, whereas physical limitation score was directly related (P≤0.05 for all). However, only biometric measures (step count and heart rate) were associated with u-hs-cTnI (inversely related, P<0.05), while only the psychometric measures of physical limitation were associated with hs-CRP (directly related, P≤0.05). Conclusions In stable ischemic heart disease patients, remotely monitored measures were associated with MACE risk biomarkers. Both biometric and psychometric measures were related to NT-proBNP. In contrast, biometric measures were uniquely related to u-hs-cTnI, while psychometric indices were uniquely related to hs-CRP. Further investigation could assess the predictive value of these metrics for MACE in ischemic heart disease.