Pericardial fat volume is related to endothelial-mediated coronary blood flow in women with suspected coronary microvascular dysfunction. A report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study.

Background: Coronary microvascular dysfunction is prevalent in women with signs and symptoms of ischemia but no obstructive coronary artery disease (CAD) and is associated with an adverse prognosis. Elevated pericardial fat volume predicts adverse cardiac events, but mechanistic pathways of the association are not well understood. Methods: 118 women enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study with suspected coronary microvascular dysfunction but no obstructive CAD underwent adenosine stress 1.5 T cardiovascular magnetic resonance imaging (CMR) imaging and invasive coronary reactivity testing. Semi-quantitative myocardial perfusion reserve index (MPR) index was derived from perfusion images. Pericardial fat volume was measured by manually contouring the cardiac margins and adjacent adipose tissue on a single trans-axial HASTE slice at the level of the left main coronary artery origin and indexed to body surface-area. Simple standard deviation analysis obtained for continuous variables and frequency (percent) for categorical variables. The relationships between pericardial fat volume and coronary reactivity testing parameters were examined by correlation and multivariable regression analyses. Results: Women with suspected coronary microvascular dysfunction had a mean age of 55 ± 10 years, body mass index (BMI) of 28 ± 7 kg/m2, 44 % had a history of smoking, 63 % hypertension, 8 % diabetes, and 20 % dyslipidemia. CMR imaging-derived pericardial fat volume and coronary blood flow response to intracoronary acetylcholine (Δ CBF) were negatively correlated (r = -0.32, p = 0.0013). After adjustment for age, number of risk factors, high-density lipoprotein (HDL), and cold pressor diameter response, pericardial fat volume remained a significant predictor of Δ coronary blood flow (p = 0.04). There was no association with other coronary reactivity testing measures or CMRI derived MPR index. Conclusions: Among women with suspected coronary microvascular dysfunction but no obstructive CAD, pericardial fat volume appears to be related in a hypothesized adverse direction to coronary microvascular endothelial function. These results support further work confirming and extending these results to investigate pericardial fat volume as mechanistic pathway and potential treatment target for coronary microvascular dysfunction-related adverse events.Trial registration: clinicaltrials.govNCT00832702.

Comparison of risk profiles of participants in the Women's IschemiA TRial to reduce events in non-ObstRuctive CAD (WARRIOR) trial, using coronary computed tomography angiography vs invasive coronary angiography.

OBJECTIVE: To compare baseline characteristics of participants in the Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR) trial by qualification by Coronary Computed Tomography Angiography (CCTA) or Invasive Coronary Angiography (ICA). METHODS: The WARRIOR trial (NCT03417388) is an ongoing multicenter, prospective, randomized, blinded outcome evaluation of intensive medical therapy vs. usual care in women with suspected Ischemia and No Obstructive Coronary Artery Disease (INOCA) identified by either CCTA or ICA on the outcome of major adverse cardiovascular events (MACE). No coronary artery disease is defined as <50% luminal stenosis and normal coronary arteries is defined as no evidence of atherosclerosis including calcified and non-calcified plaque. Data presented was extracted on May 27, 2020. No clinical outcomes were assessed. RESULTS: An initial sample cohort of 797 women was included. The majority were younger than 65 years, White participants (73.3%), 159 had diabetes (19.9%), and 676 had angina (84.8%) with the remainder having symptoms of suspected ischemic heart disease. Over 50% of randomized participants had normal coronaries without luminal irregularities by ICA or CCTA. Participants randomized to ICA were more likely to have worse baseline clinical risk profiles with older age, higher burden of cardiac risk factors and poor quality of life with disabling angina. CONCLUSIONS: Among this initial sample of women with suspected INOCA randomized in the WARRIOR trial, there is a differential baseline cardiac risk of participants enrolled after CCTA or ICA. However, the majority had no evidence of atherosclerotic plaque or obstructive stenosis, after evaluation by ICA or CCTA. These results suggest that non-invasive evaluation with CCTA is likely to be associated with lower risk of MACE.

Elevated high-density lipoprotein cholesterol and adverse outcomes in women with symptoms of ischemic heart disease.

Background: Emerging data in the general population and those with coronary artery disease demonstrate higher risk of adverse outcomes with high (>70 mg/dL) HDL-C levels. There are limited data on the risk of adverse outcomes in women with suspected ischemic heart disease. Objective: To investigate relationships between high (>70 mg/dL), average (50-70 mg/dL), and low (<50 mg/dL) HDL-C levels with major adverse cardiac events (MACE) (death, myocardial infarction, stroke, and heart failure hospitalization), and all-cause mortality in women referred for coronary angiography for suspected myocardial ischemia. Methods: A total of 607 women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) original cohort (NCT00000554) with available HDL-C values were included in this analysis. Associations between HDL-C level and outcomes were evaluated using both multivariate Cox proportional hazard regression and spline regression analysis. Results: The mean age was 59 ± 12 years, 62 % had 3 or more cardiac risk factors, and 66 (10.9 %) had a high HDL-C. High and low HDL-C were both associated with higher MACE risk compared to average HDL-C after adjusting for demographic and clinical characteristics (HR 1.80, CI 1.03-3.14, p = 0.038; HR 1.63, CI 1.09-2.42, p = 0.016, respectively). Similarly, high, and low HDL-C were associated with higher risk of all-cause mortality (HR 3.64, CI 1.84-7.20, p < 0.001; HR 2.81, CI 1.67-4.71, p < 0.001, respectively). Conclusions: High and low HDL-C levels are both independently associated with higher MACE and all-cause mortality in women with suspected ischemia undergoing coronary angiography.

Clinical aspects of ischemia with no obstructive coronary artery disease (INOCA).

Ischemia with no obstructive coronary arteries (INOCA) is defined as patients with evidence of myocardial ischemia without obstructive coronary artery disease. About 3-4 million people in the United States have INOCA, more commonly affecting women, and carries adverse morbidity, mortality, and relatively high healthcare costs. The pathophysiology of INOCA appears to be multi-factorial with a variety of contributing mechanisms. Diagnosis of INOCA is suggested by non-invasive or invasive testing consistent with myocardial ischemia. Due to the high prevalence of coronary risk factors and atherosclerosis in the INOCA population, current treatment strategies target angina, coronary atherosclerosis, and atherosclerotic risk factors, as well as burgeoning treatment of coronary microvascular dysfunction (CMD). Ongoing clinical trials are assessing different options.

α-Ketoglutarate-Dependent KDM6 Histone Demethylases and Interferon-Stimulated Gene Expression in Lupus.

OBJECTIVE: We aimed to investigate the hypothesis that interferon (IFN)-stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression. METHODS: Monocytes from healthy volunteers and patients with SLE at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation, and gene expression. The histone demethylases KDM6A/B were inhibited using glycogen synthase kinase J4 (GSK-J4). GSK-J4 was tested in pristane and resiquimod (R848) models of IFN-driven SLE. RESULTS: SLE monocytes had enhanced rates of glycolysis and oxidative phosphorylation compared to healthy control monocytes, as well as increased levels of isocitrate dehydrogenase and its product, α-ketoglutarate (α-KG). Because α-KG is a required cofactor for histone demethylases KDM6A and KDM6B, we hypothesized that IFNα may be driving "trained immune" responses through altering histone methylation. IFNα priming (day 1) resulted in a sustained increase in the expression of ISGs in primed cells (day 5) and enhanced expression on restimulation with IFNα. Importantly, decreased H3K27 trimethylation was observed at the promoters of ISGs following IFNα priming. Finally, GSK-J4 (KDM6A/B inhibitor) resulted in decreased ISG expression in SLE patient monocytes, as well as reduced autoantibody production, ISG expression, and kidney pathology in R848-treated BALB/c mice. CONCLUSION: Our study suggests long-term IFNα exposure alters the epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting trained immunity to type I IFN. Importantly, it opens the possibility that targeting histone-modifying enzymes, such as KDM6A/B, may reduce IFN responses in SLE.

Dietary Composition, Angiographic Coronary Disease, and Cardiovascular Outcomes in the WISE Study (Women's Ischemia Syndrome Evaluation).

BACKGROUND: Studies relating diet to angiographic coronary artery disease (CAD) and subsequent major adverse cardiac events (MACE) in women are limited. Information on diet was collected in the Women's Ischemia Syndrome Evaluation (WISE), a prospective cohort study of symptomatic women referred for coronary angiography to evaluate suspected ischemic heart disease. METHODS: A consecutive subgroup (n = 201 of 936) of enrolled women completed the modified Block food frequency questionnaire (FFQ). Data on outcomes were collected and adjudicated after 8-year follow-up. A set of logistic regression models were fitted for non-obstructive versus obstructive coronary stenosis (<50% versus ≥50%). Cox proportional hazard regression models were fitted for outcomes, with each dietary composition variable adjusted for the degree of coronary stenosis. RESULTS: At baseline, the subgroup cohort was 58 ± 12 years old with a body mass index (BMI) of 30 ± 7 kg/m2. An increased proportion of calories consumed from protein was associated with higher levels of baseline obstructive coronary stenosis. Those individuals who ate a higher amount of protein, carotene, and servings of vegetables and meat, however, were each associated with lower subsequent adverse outcomes, respectively. CONCLUSIONS: Among women undergoing coronary angiography for suspected CAD, a higher percentage of protein intake was associated with higher baseline stenosis severity; however, the amount of protein intake, vegetable, meat, and carotene intake, was conversely associated with subsequent lower adverse cardiovascular outcome risk.

MINOCA: Diagnostic work-up, risk stratification and tailored therapies.

Myocardial infarction with no obstructive coronary artery disease (MINOCA) diagnostic work-up, risk stratification and tailored therapies are emerging as the recognition of this type of MI is increasingly recognized. Diagnostic workup using advanced imaging can include coronary angiography/intravascular ultrasound (IVUS)/optical coherent tomography (OCT), echo and cardiac magnetic resonance imaging (MRI). Risk stratification portends an intermediate risk compared to multivessel obstructive coronary artery disease (CAD). While event rates are high enough to warrant concern, they are relatively low enough to require trials with large sample sizes and hard outcomes. Tailored therapies include common sense therapeutic lifestyle change (TLC) and optimal medical therapy (OMT) due to the high prevalence of non-obstructive CAD, however therapeutic clinical trials are needed. Currently one large outcome trial in ischemia with no obstructive coronary artery disease (INOCA) is ongoing.

Psychosocial Factors of Women Presenting With Myocardial Infarction With or Without Obstructive Coronary Arteries.

BACKGROUND: Women with myocardial infarction (MI) are more likely to have elevated stress levels and depression than men with MI. OBJECTIVES: We investigated psychosocial factors in women with myocardial infarction with nonobstructive coronary arteries (MINOCA) and those with MI and obstructive coronary artery disease (CAD). METHODS: Women with MI enrolled in a multicenter study and completed measures of perceived stress (Perceived Stress Scale-4) and depressive symptoms (Patient Health Questionnaire-2) at the time of MI (baseline) and 2 months later. Stress, depression, and changes over time were compared between MI subtypes. RESULTS: We included 172 MINOCA and 314 MI-CAD patients. Women with MINOCA were younger (age 59.4 years vs 64.2 years; P < 0.001) and more diverse than those with MI-CAD. Women with MINOCA were less likely to have high stress (Perceived Stress Scale-4 ≥6) at the time of MI (51.0% vs 63.0%; P = 0.021) and at 2 months post-MI (32.5% vs 46.3%; P = 0.019) than women with MI-CAD. There was no difference in elevated depressive symptoms (Patient Health Questionnaire-2 ≥2) at the time of MI (36% vs 43%; P = 0.229) or at 2 months post-MI (39% vs 40%; P = 0.999). No differences in the rate of 2-month decline in stress and depression scores were observed between groups. CONCLUSIONS: Stress and depression are common among women at the time of and 2 months after MI. MINOCA patients were less likely to report high stress compared with MI-CAD patients, but the frequency of elevated depressive symptoms did not differ between the 2 groups. Stress and depressive symptoms decreased in both MI-CAD and MINOCA patients over time.

Reduced left ventricular function on cardiac MRI of SLE patients correlates with measures of disease activity and inflammation.

Background: Women with SLE have an elevated risk of cardiovascular disease. Many women with SLE frequently report chest pain in the absence of obstructive coronary artery disease (CAD) due to coronary microvascular dysfunction (CMD), a form of ischemia with no obstructive CAD. Echocardiographic studies have shown that SLE patients have reduced left ventricular (LV) function, which may also correlate with higher SLE disease activity scores. As such, we used cardiac magnetic resonance imaging (cMRI) to investigate the relationship between SLE, related inflammatory biomarkers, and cardiac function in female SLE patients. Methods: We performed stress cMRI in women with SLE and chest pain with no obstructive CAD (n=13, all met ACR 1997 criteria,) and reference controls (n=22) using our published protocol. We evaluated LV function, tissue characterization (T1 mapping, ECV), and delayed enhancement, using CV142 software (Circle Cardiovascular Imaging Inc, Calgary, AB, Canada). Myocardial perfusion reserve index (MPRI) was calculated using our published protocol. SLEDAI and SLICC Damage Index (DI) were calculated per validated criteria. Serum samples were analyzed for inflammatory markers and autoantibodies. Wilcoxon rank-sum test was performed on clinical values with CMD and no CMD SLE subjects, and on cMRI values with all SLE subjects and controls. Correlation analysis was done on clinical values, and cMRI values on all SLE subjects. Results: Overall, 40% of SLE subjects had MPRI values < 1.84, consistent with CMD. Compared to controls, SLE subjects had significantly lower LVEF, and higher LVESVi and LVMi. Corresponding to this, radial, longitudinal, and circumferential strain were significantly lower in the SLE subjects. In correlation analysis of serum inflammatory biomarkers to cMRI values in the SLE subjects, SLICC DI was related to worse cardiac function (lower radial, circumferential and longitudinal strain) and higher T1 time. Additionally, fasting insulin and ESR were negatively correlated with LVMi. Fasting insulin also negatively correlated with ECV. CRP had a positive association with LVESV index and CI and a negative association with longitudinal strain. Conclusions: Among women with SLE with chest pain and no obstructive CAD, 40% have CMD. While evaluations of known inflammatory markers (such as CRP and ESR) predictably correlated with decreased cardiac function, our study found that decreased fasting insulin levels as a novel marker of diminished LV function. In addition, low insulin levels were observed to correlate with increased LVMi and ECV, suggesting a cardioprotective effect of insulin in SLE patients. We also noted that SLICC DI, an assessment of SLE damage, correlates with cardiac dysfunction in SLE. Our findings underline the potential of non-invasive cMRI as a tool for monitoring cardiovascular function in SLE, particularly in patients with high SLICC DI, ESR and CRP and low fasting insulin levels.

Invasive Coronary Assessment in Myocardial Ischemia with No Obstructive Coronary Arteries.

PURPOSE OF REVIEW: The purpose of this review is threefold: (i) to give an overview of well-established invasive methods for assessing patients with ischemia with no obstructive coronary arteries (INOCA) in the cardiac catheterization laboratory; (ii) to describe the prognostic and treatment implications based on these findings, and (iii) to discuss current knowledge gaps and future perspectives. RECENT FINDINGS: Recent studies have demonstrated that invasive coronary function testing not only allows for risk stratification of patients with INOCA but also guides medical therapy with improvement in symptoms and quality of life. Based on these findings, invasive coronary function assessment is now a class 2a recommendation in the 2021 ACC/AHA chest pain guideline to improve the diagnosis of coronary microvascular dysfunction and to enhance risk stratification. Invasive functional testing for patients with INOCA is well established and easily performed in the catheterization laboratory. Comprehensive invasive assessment is a key to differentiating INOCA endotypes and optimizing both medical therapy and preventive strategies including lifestyle modification.

Sex Differences in Quality of Life in Patients with Ischemia with No Obstructive Coronary Artery Disease (INOCA): A Patient Self-Report Retrospective Survey from INOCA International.

Women with obstructive coronary artery disease (CAD) have a relatively lower quality of life (QoL) compared to men, but our understanding of sex differences in QoL in ischemia with no obstructive coronary artery disease (INOCA) is limited. We conducted a survey of patient members of INOCA International with an assessment of self-reported health measures. Functional capacity was retrospectively estimated using the Duke Activity Status Index (DASI), assessing levels of activities performed before and after INOCA symptom onset. Of the 1579 patient members, the overall survey completion rate was 21%. Women represented 91% of the respondents. Estimated functional capacity, expressed as metabolic equivalents (METs), was higher before compared to after INOCA diagnosis comparably for both women and men. For every one MET decline in functional capacity, there was a significantly greater decline in QoL for men compared with women in physical health (4.0 ± 1.1 vs. 2.9 ± 0.3 days/month, p < 0.001), mental health (2.4 ± 1.2 vs. 1.8 ± 0.3 days/month, p = 0.001), and social health/recreational activities (4.1 ± 1.0 vs. 2.9 ± 0.3 days/month, p = 0.0001), respectively. In an international survey of patients living with INOCA, despite similar diagnoses, clinical comorbidities, and symptoms, INOCA-related functional capacity declines are associated with a greater adverse impact on QoL in men compared to women.

Inpatient Neurology Deaths and Factors Associated With Discharge to Hospice.

Background and Purpose: The Neurology Mortality Review Committee at our institution identified variability in location of death for patients on our inpatient neurology services. Hospice may increase the number of patients dying in their preferred locations. This study aimed to characterize patients who die on inpatient neurology services and explore barriers to discharge to hospice. Methods: This retrospective study was completed at a single, quaternary care medical center that is a Level I Trauma Center and Comprehensive Stroke Center. Patients discharged by an inpatient neurology service between 6/2019-1/2021 were identified and electronic medical record review was performed on patients who died in the hospital and who were discharged to hospice. Results: 69 inpatient deaths and 74 discharges to hospice occurred during the study period. Of the 69 deaths, 54 occurred following withdrawal of life sustaining treatment (WLST), of which 14 had a referral to hospice placed. There were 88 "hospice-referred" patients and 40 "hospice-eligible" patients. Hospice-referred patients were less likely to require the intensive care unit than hospice-eligible patients. Hospice-referred patients had their code status changed to Do Not Intubate earlier and were more likely to have advanced directives available. Conclusion: Our data highlight opportunities for further research to improve discharge to hospice including interhospital transfers, advanced directives, earlier goals of care discussions, palliative care consultations, and increased hospice bed availability. Importantly, it highlights the limitations of using in-hospital mortality as a quality indicator in this patient population.

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.

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.