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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 obstructive 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., Competing Interests: Declaration of competing interest CNBM serves as Board of Director for iRhythm and receives personal fees paid to CSMC bySHL Telemedicine. CJP receives research grants from GE Healthcare, Merck, Sanofi, CLS Behring, BioCardia, McJunkin Family Foundation Trust, Brigham & Women's Hospital, Gatorade Trust through the University of Florida Department of Medicine, and Mesoblast, Inc.; has received consultant fees/honoraria from Verily Life Sciences. LLC Project Baseline OSMB (Google), Ironwood, XyloCor, Slack Inc., Elsevier, Imbria Pharmaceuticals, Milestone Pharmaceuticals Inc., AstraZeneca Pharmaceuticals, and Sanofi-Aventis. SL has no disclosures. MB has received grant support from NIH and GE. GC has no disclosures. LS has received honoraria for speaking from Elucid Bioimaging and Heartflow., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFpEF) is the most common cardiac complication in patients with coronary microvascular dysfunction (CMD), yet its underlying pathways remain unclear. Aortic pulse-wave velocity (aPWV) is an indicator of large artery stiffness and a predictor for cardiovascular disease. However, aPWV in CMD and HFpEF is not well characterized and may provide understanding of disease progression., Methods: Among participants without obstructive coronary artery disease, we evaluated 51 women with suspected CMD and 20 women and men with evidence of HFpEF. All participants underwent aPWV measurement (SphygmoCor, Atcor Medical) with higher aPWV indicating greater vascular stiffness. Cardiac magnetic resonance imaging (CMRI) assessed left ventricular (LV) ejection fraction, CMD via myocardial perfusion reserve index (MPRI), and ventricular remodeling via LV mass-volume ratio. . Statistical analysis was performed using Wilcoxon rank sum tests, Pearson correlations and linear regression analysis., Results: Compared to the suspected CMD group, the HFpEF participants were older (65 ± 12 vs 56 ± 11 yrs., p  = 0.002) had higher BMI (31.0 ± 4.3 vs 27.8 ± 6.7 kg/m 2 , p  = 0.013), higher aPWV (10.5 ± 2.0 vs 8.0 ± 1.6 m/s, p  = 0.05) and lower MPRI (1.5 ± 0.3 vs1.8 ± 0.3, p  = 0.02), but not remodeling. In a model adjusted for cardiovascular risk factors, the HFpEF group had a lower LVEF (estimate -4.78, p  = 0.0437) than the suspected CMD group., Conclusions: HFpEF participants exhibit greater arterial stiffness and lower myocardial perfusion reserve, with lower LVEF albeit not remodeling, compared to suspected CMD participants. These findings suggest arterial stiffness may contribute to progression from CMD to HFpEF. Prospective work is needed and ongoing., Competing Interests: Dr. Bairey Merz has disclosures from iRhythm and SHL Telemedicine. Dr. Pepine: Research Grant from Gilead Sciences, Inc., Pfizer, Park-Davis, Sanofi-Aventis, Fujisawa HealthCare Inc., Baxter, Brigham & Women's Hospital, AstraZeneca, NIH/NHLBI, Amorcyte/Neostem, Cytori, InfraReDx, NHLBI/NCRR CTSA grant 1UL1RR029890, AHA. Consultant/Advisory Board: NIH Study Section of Cardiovascular Sciences Small Business Activities 2RG1 CVS-K-10, Lilly/Cleveland Clinic DSMB Member for a Phase 2 Efficacy and Safety Study of Ly2484595, Medtelligence, NHLBI Study Section for Progenitor Cell Biology Consortium, NHLBI DSMB Chair for Freedom Trial. Dr. Handberg receives research grants from Aastrom Biosciences, Amorcyte, Biocardia, Brigham and Women's Hospital, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Duke Clinical Research Institute, East Carolina University, Everyfit Inc., Medtronic, Merck & Co., Mesoblast, National Institutes of Health (NIH), NIH through University of Rochester, NIH through Brigham and Women's Health, NIH through University of Texas, PCORI, and Sanofi Aventis; Research grant and educational grant from Gilead Sciences; Unrestricted educational grants for the Vascular Biology Working Group from Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Ionis, and Relypsa; and Consultant fees from Bristol-Myers Squibb Company. Dr. C. Noel Bairey Merz, serve as Board of Director for iRhythm, fees paid through CSMC from Abbott Diagnostics and SHL Telemedicine. Dr. Janet Wei served on an advisory board for Abbott Vascular. All other authors have no disclosures to disclose., (© 2024 The Authors.)

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/m 2 . 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.

Minocycline, an anti-inflammatory antibiotic drug, rebalances impaired gut microbiota, attenuates neuroinflammation and lowers high blood pressure in animal models of hypertension and in hypertensive patients. Our objective in this study was to investigate if antihypertensive effects of minocycline involve the expression of gut epithelial genes relevant to blood pressure homeostasis using human colonic 3-dimensional organoid culture and high-throughput RNA sequencing. The data demonstrates that minocycline could restore impaired expression of functional genes linked to viral and bacterial immunity, inflammation, protein trafficking and autophagy in human hypertensive organoids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Identifying ischemic heart disease (IHD) in women based on symptoms is challenging. Women are more likely to endorse non-cardiac symptoms. More than 50% of women with suspected ischemia have no obstructive coronary disease (and thus, INOCA) and impaired outcomes during follow-up. We aimed to identify symptoms having predictive capacity for INOCA in women with clinical evidence of coronary ischemia. We included 916 women from the original WISE cohort (NCT00000554) who had coronary angiography performed for suspected ischemia and completed a 65-item WISE symptom questionnaire. Sixty-two percent ( n = 567) had suspected INOCA. Logistic regression models using a best subsets approach were examined to identify the best predictive model for INOCA based on Score χ 2 and AICc. A 10-variable, best-fit model accurately predicted INOCA (AUC 0.72, 95% CI 0.68, 0.75). The model indicated that age ≤ 55 years, left side chest pain, chest discomfort, neck pain, and palpitations had independent, positive relationship (OR > 1) to INOCA ( p < 0.001 to 0.008). An inverse relationship (OR < 1) was observed for impending doom, and pain in the jaw, left or bilateral arm, and right hand, interpreted as INOCA associated with the absence of these symptoms ( p ≤ 0.001 to 0.023). Our best-fit model accurately predicted INOCA based on age and symptom presentation ~72% of the time. While the heterogeneity of symptom presentation limits the utility of this unvalidated 10-variable model, it has promise for consideration of symptom inclusion in future INOCA prediction risk modeling for women with evidence of symptomatic ischemia.

Background: Studies on the longitudinal effects of intense physical training on cardiac remodeling are limited, especially in American collegiate football players., Hypothesis: College-level American football training will result in remodeling in a pattern consistent of a sport with moderate static and dynamic demands with increases in both wall and chamber sizes., Methods: We studied 85 American collegiate football players who underwent transthoracic echocardiogram (TTE) for asymptomatic or mild COVID-19-related illness and compared the changes in echo dimensions to their preparticipation screening TTE. Pre- and posttraining variables were compared using a paired t-test for normally distributed variables., Results: Mean age was 19 years ± 1 and 61% of athletes were Black. Mean follow-up between TTEs was 21 ± 13 months. There was an increase in left atrial volume index (26.4 ± 5.5 to 32.8 ± 8.4 mL/m 2 , p < .001), LV end diastolic diameter (5.13 ± 0.4 to 5.27 ± 0.4 cm, p = .003), basal RV diameter (3.28 ± 0.7 to 3.83 ± 0.5 cm, p = <.001), LV mass index (86.7 ± 15.3 to 90.1 ± 15.3, p = .015), and aortic root diameter (3.1 ± 0.4 to 3.2 ± 0.3 cm, p = .03) from pre- to posttraining, with a slightly greater magnitude in athletes with >2 years of training. Presence of left atrial enlargement (≥35 mL/m 2 ) increased from 2.9% to 29% pre- to postparticipation in athletes with >2 years training. No significant changes in wall thickness, diastolic function, or right ventricular systolic function were observed., Conclusion: American football players college-level training was associated with increases in left and right ventricular chamber sizes, left atrial size, and aortic root diameter., (© 2023 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Background: While autoimmune rheumatic diseases (ARDs) have been linked with coronary microvascular dysfunction (CMD), the relationship between ARD and CMD in women with signs and symptoms of ischemia and no obstructive arteries (INOCA) are not well described. We hypothesized that among women with CMD, those with ARD history have greater angina, functional limitations, and myocardial perfusion compromise compared to those without ARD history., Methods: Women with INOCA and confirmed CMD by invasive coronary function testing were included from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project (NCT00832702). Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI), and cardiac magnetic resonance myocardial perfusion reserve index (MPRI) were collected at baseline. Chart review was performed to confirm self-reported ARD diagnosis., Results: Of the 207 women with CMD, 19 (9%) had a confirmed history of ARD. Compared to those without ARD, women with ARD were younger ( p  = 0.04). In addition, they had lower DASI-estimated metabolic equivalents ( p  = 0.03) and lower MPRI ( p  = 0.008) but similar SAQ scores. There was a trend towards increased nocturnal angina and stress-induced angina in those with ARD ( p  = 0.05 for both). Invasive coronary function variables were not significantly different between groups., Conclusions: Among women with CMD, women with a history of ARD had lower functional status and worse myocardial perfusion reserve compared to women without ARD. Angina-related health status and invasive coronary function were not significantly different between groups. Further studies are warranted to understand mechanisms contributing to CMD among women with ARDs with INOCA., Competing Interests: CB, serves as Board of Director for iRhythm, fees paid through CSMC from Abbott Diagnostics and Sanofi. JW served on an advisory board for Abbott Vascular. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Chen, Chang, Manchanda, Cook-Wiens, Shufelt, Anderson, Petersen, Naik, Thomson, Berman, Handberg, Pepine, Bairey Merz and Wei.)

Since 1996, the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) has been investigating pathophysiological processes underlying ischemic heart disease in women and related outcomes. Recent findings have focused on women with signs and symptoms of ischemia and no obstructive coronary arteries (INOCA) and their elevated risk for heart failure with preserved ejection fraction (HFpEF). This review summarizes the latest WISE findings related to INOCA and pre-HFpEF characteristics, addressing our understanding of contributions from traditional vs nontraditional risk factors in women., Competing Interests: Dr. Bairey Merz serves on the Board of Directors for iRhythm and consultant for Sanofi and Abbott Diagnostics. Dr. Wei serves on an advisory board for Abbott Vascular. All other authors report no disclosures., (Copyright: © 2023 The Author(s). Published by IMR Press.)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Hypertension (HTN) is associated with gut dysbiosis and the depletion of butyrate-producing bacteria in animal models and people. Furthermore, fecal material transfer from donor hypertensive patients increases blood pressure in normotensive recipient animals and ameliorates HTN-associated pathophysiology. These observations have implications in the impaired interactions between the gut and gut microbiota in HTN. Although this concept is supported in animal models, little is known about human HTN. Therefore, our objective for this study was to compare gene expression with transcriptomics and its potential to influence microbiota in subjects with normal and high blood pressure (HBP). Colon samples from reference subjects with normal blood pressure (REF) and HBP were used for RNA-seq to analyze their transcriptomes. We observed the significant downregulation of gene sets governing immune responses (e.g., SGK1 and OASL ), gut epithelial function (e.g., KRT20 and SLC9A3R1 ), gut microbiota (e.g., PPARG and CIDEC ) and genes associated with cardiovascular and gut diseases (e.g., PLAUR and NLN ) in HBP subjects; the expression of genes within these pathways correlated with blood pressure. Potential drug targets in the gut epithelium were identified using the Drug Gene International Database for possible use in HTN. They include peroxisome proliferator-activated receptor gamma ( PPRG), active serum/glucocorticoid regulated kinase 1 (SGK1) and 3 beta-hydroxysteroid isomerase type II inhibitor (HSD3B). Finally, butyrate, a microbiota-derived short-chain fatty acid, restored the disrupted expression of certain functional genes in colonic organoids from HBP subjects. Patients with HBP exhibit a unique transcriptome that could underlie impaired gut-microbiota interactions. Targeting these interactions could provide a promising new therapeutic intervention for hypertension management.

Study Objective: Sudden cardiac death is the most common cause of non-traumatic death in collegiate athletes. Marfan syndrome poses a risk for sudden cardiac death secondary to aortic root dilation leading to aortic dissection or rupture. Arm span to height ratio (ASHR) > 1.05 has been proposed as a screening tool for Marfan syndrome in pre-participation examinations (PPE) for collegiate athletes but limited data exists on the association between ASHR and aortic root diameter (ARD). This study examines the relationship between ASHR and ARD and assesses for predictors of ARD., Design: Retrospective chart review., Setting: National Collegiate Athletic Association Division I University., Participants: 793 athletes across thirteen sports between 2012 and 2022 evaluated with PPE and screening echocardiogram., Interventions: Not applicable., Main Outcome Measures: (1) Relationships between ASHR, SBP, BSA, and ARD amongst all athletes as well as stratified by ASHR >1.05 or ≤1.05 using univariate analysis. (2) Predictors of ARD using multivariate analysis using linear regression., Results: 143 athletes (18 %) had ASHRs > 1.05. Athletes with ASHR > 1.05 had higher ARD (2.99 cm) than athletes with ASHR ≤ 1.05 (2.85 cm). Weak correlations were noted between ASHR, ARD, and SBP. Multivariate analysis showed that BSA, male sex, and participation in swimming were predictors of ARD. ASHR was not predictive of ARD in regression analysis., Conclusions: These findings showed a tendency towards higher ARD in athletes with ASHR >1.05 but this observation was not statistically significant in multivariate analysis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Ischemic heart disease (IHD) risk in women includes biomedical, behavioral, and psychosocial contributors. The purpose of this study was to build upon previous research suggesting that in women, somatic symptoms (SS) of depression may be important to the development of IHD risk factors and major adverse cardiovascular events (MACE). Based on previous findings, we hypothesized that: (1) SS would be associated with robust biomedical predictors of heart disease and functional capacity, while cognitive symptoms (CS) of depression would not, and (2) SS would independently predict adverse health outcomes while CS would not., Methods: We examined the relationships between symptoms of depression (SS/CS), metabolic syndrome (MetS), inflammatory markers (IM), coronary artery disease (CAD) severity, and functional capacity in two independent cohorts of women with suspected IHD. In the Women's Ischemia Syndrome Evaluation (WISE), we also examined these variables as predictors of all-cause mortality (ACM) + MACE over a median 9.3-year follow-up. The WISE sample included 641 women with suspected ischemia with or without obstructive CAD. The WISE-Coronary Vascular Dysfunction (WISE-CVD) sample consisted of 359 women with suspected ischemia and no obstructive CAD. All study measures were collected uniformly at baseline. Depressive symptoms were measured via the Beck Depression Inventory. MetS was assessed according to Adult Treatment Panel III (ATP-III) criteria., Results: In both studies, SS was associated with MetS (Cohen's d = 0.18, 0.26, P < 0.05, respectively), while CS was not. Within WISE, using Cox Proportional Hazard Regression, SS (Hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 1.01-1.15; HR = 1.07, 95% CI = 1.00-1.13) and MetS (HR = 1.89, 95% CI = 1.16-3.08; HR = 1.74, 95% CI=1.07-2.84) were independent predictors of ACM + MACE after controlling for demographics, IM, and CAD severity, while CS was not., Conclusions: In two independent samples of women undergoing coronary angiography due to suspected ischemia, SS but not CS of depression were associated with MetS, and both SS and MetS independently predicted ACM and MACE. These results add to previous studies suggesting that SS of depression may warrant specific attention in women with elevated cardiovascular disease (CVD) risk. Future research evaluating the biobehavioral basis of the relationship between depression, MetS, and CVD is needed., Competing Interests: Conflicts of interest There are no conflicts of interest.

Background: Cardiac remodeling is a process mediated, in part, by 18-hydroxyeicosapentaenoic acid (HEPE), a metabolite of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA). We hypothesized that trans-myocardial levels of 18-HEPE could inform the pathophysiologic processes involved in heart failure with preserved ejection fraction (HFpEF)., Methods: We measured the concentration of 18-HEPE and EPA in trans-myocardial plasma samples from 10 subjects enrolled in The Women's Ischemia Syndrome Evaluation [WISE] Mechanisms of Coronary Microvascular Dysfunction Leading to Pre-HFpEF project., Results: Concentrations of 18-HEPE were significantly lower in coronary venous compared to the aortic plasma (270.5 pg/mL [212.8-480.8] vs. 430.5 pg/mL [299.5-655.8], p = 0.0039). There was a significant correlation between the concentrations of coronary venous EPA and aortic 18-HEPE ( r = 0.94, p = 0.0002), and aortic EPA and aortic 18-HEPE ( r = 0.82, p = 0.0058)., Conclusions: Results of this small pilot study support the suggestion that 18-HEPE is synthesized outside the heart and utilized within the myocardial bed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Microvascular dysfunction describes a varied set of conditions that includes vessel destruction, abnormal vasoreactivity, in situ thrombosis, and fibrosis, which ultimately results in tissue damage and progressive organ failure. Microvascular dysfunction has a wide array of clinical presentations, ranging from ischemic heart disease to renal failure, stroke, blindness, pulmonary arterial hypertension, and dementia. An intriguing unifying hypothesis suggests that microvascular dysfunction of specific organs is an expression of a systemic illness that worsens with age and is accelerated by vascular risk factors. Studying relationships across a spectrum of microvascular diseases affecting the brain, retina, kidney, lung, and heart may uncover shared pathologic mechanisms that could inform novel treatment strategies. We review the evidence that supports the notion that microvascular dysfunction represents a global pathologic process. Our focus is on studies reporting concomitant microvascular dysfunction of the heart with that of the brain, kidney, retina, and lung., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Left ventricular assist device (LVAD) implantation provides a robust survival advantage, however despite improvements in mortality, the adverse event burden of durable mechanical circulatory support remains high. Bleeding complications are one such significant complication. The uSTOP LVAD BLEED (Utilization of umbilical cord lining Stem cells TO Prevent LVAD associated angiodysplastic BLEEDing) pilot study is designed to evaluate the safety and tolerability of escalating doses of umbilical cord lining stem cells (ULSCs) in LVAD recipients to ameliorate the dysregulation of angiogenic factors seen in this population., Design: This Phase Ia single-ascending dose pilot study will evaluate the IV administration of ULSCs in stable out-patients supported with an LVAD. In a 3 + 3 design, a maximum of 18 patients will receive an IV infusion of ULSCs., Main Outcome Measures: The primary endpoints are safety and tolerability, secondary exploratory endpoints will include biomarker evaluation of angiogenic dysregulation., Summary: This represents a novel cell type and route of administration in this population, while collecting initial data regarding the magnitude and duration of effects of cell therapy, and assessing the possibility of decreasing bleeding by a strategy of vascular stabilization., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04811261. https://clinicaltrials.gov/ct2/show/NCT04811261., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Coronary microvascular dysfunction is a ubiquitous pathologic process that is operational in ischemia with no obstructive coronary artery disease and other cardiovascular disorders including heart failure with preserved ejection fraction. It may, in fact, be a manifestation of a multi-systemic condition of small vessel dysfunction that also affects the brain and kidneys. While the pathophysiology driving coronary microvascular dysfunction is multifactorial, chronic inflammation plays an important role. Resolution of inflammation is an active process mediated, in part, by a family of locally active mediators biosynthesized from omega-3 fatty acids, collectively referred to as specialized pro-resolving mediators. Omega-3 fatty acid treatment modulates inflammation and is associated with improved cardiovascular outcomes and attenuation of plaque progression on cardiovascular imaging. Whether omega-3 fatty acid treatment attenuates coronary microvascular dysfunction is unknown., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: There is a paucity of data describing the association between blood pressure (BP) and cardiac remodeling in female collegiate athletes., Methods: This retrospective cohort review describes the BP characteristics and echocardiographic features of female collegiate athletes during preparticipation evaluation. We evaluated data from 329 female athletes at two National Collegiate Athletic Association (NCAA) Division I universities who underwent preparticipation evaluation that included medical history, physical examination, 12-lead electrocardiography, and 2-dimensional transthoracic echocardiography. BP values were divided into categories of normal, elevated, stage 1 and stage 2 hypertension based on 2017 ACC/AHA Guidelines. Left ventricular mass index was calculated and indexed to body surface area and further classified into concentric remodeling, concentric hypertrophy, and eccentric hypertrophy., Results: Normal BP values were noted in 184 (56%) female athletes, 88 (26.7%) had elevated BP and 57 (17.3%) had BP values indicating stage 1 or 2 hypertension. The majority of participants were white (n = 136, 73.9%). There was significantly higher body surface area in female athletes with higher BP values: 1.85 ± 0.18 in the stage 1 and 2 hypertension range, 1.82 ± 0.18 in the elevated BP range versus 1.73 ± 0.16 in the normal BP range (p < 0.001)., Conclusions: There was a trend toward higher incidence of concentric and eccentric hypertrophy in athletes with higher than normal BP, however no statistical significance was noted. Elevated BP values were frequent among female collegiate athletes, and there is evidence of cardiac remodeling associated with higher BP values., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Resolvins and maresins, members of the specialized proresolving mediator (SPM) family, are omega-3 fatty acid-derived lipid mediators that attenuate inflammation. We hypothesized that they play a role in the pathophysiology of coronary microvascular dysfunction (CMD) in women with ischemia and no obstructive coronary disease. In a pilot study, we measured the D-series resolvins (D1, D2, D3, and D5), resolvin E1, maresin 1, docosahexaenoic acid, eicosapentaenoic acid (precursor of resolvin E1), and 18-hydroxyeicosapentaenoic acid by mass spectrometry in the peripheral blood of 31 women enrolled in the Women's Ischemia Trial to Reduce Events in Nonobstructive CAD (WARRIOR) trial who had confirmed CMD assessed by coronary flow reserve. We compared SPM levels with 12 gender and age-matched reference subjects. Compared with the reference subject group, those with CMD had significantly lower plasma concentrations of resolvin D1 and maresin 1 and significantly higher levels of docosahexaenoic acid and 18-hydroxyeicosapentaenoic acid. In conclusion, insufficient or ineffective SPM production may play a role in the pathophysiology of CMD. If our results are validated in a larger cohort, omega-3 fatty acid supplementation could be tested as a novel treatment for these patients., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Study Objective: Cold Pressor Testing (CPT) is a known stimulus of the sympathetic nervous system (SNS). To better understand sympathetic contribution to coronary blood flow regulation in women with suspected ischemia and no obstructive coronary arteries (INOCA), we compared myocardial perfusion reserve during CPT stress cardiac magnetic resonance (CMR) imaging between women with suspected INOCA and reference subjects., Design: Prospective cohort., Setting: Academic hospital., Participants: 107 women with suspected INOCA and 21-age-matched reference women., Interventions: CPT stress CMR was performed with measurement of myocardial perfusion reserve index (MPRI), adjusted for rate pressure product (MPRI RPP ). Invasive coronary function testing in a subset of INOCA women (n=42) evaluated for endothelial dysfunction in response to acetylcholine, including impaired coronary diameter response ≤0% and coronary blood flow response (ΔCBF) <50%., Main Outcome Measure: MPRI RPP ., Results: Compared to reference women, the INOCA group demonstrated higher resting RPP (p=0.005) and CPT MPRI RPP (1.09±0.36 vs 0.83±0.18, p=0.002). Furthermore, INOCA women with impaired ΔCBF (n=23) had higher CPT MPRI RPP (p=0.044) compared to reference women despite lower left ventricular ejection fraction (64±7 % vs 69±2 %, p=0.005) and mass-to-volume ratio (0.79±0.15 vs 0.62±0.09, p<0.0001). These differences in CPT MPRI RPP did not persist after adjusting for age, body mass index, and history of hypertension. CPT MPRI RPP among INOCA women did not differ based on defined acetylcholine responses., Conclusions: Myocardial perfusion reserve to CPT stress is greater among women with INOCA compared to reference subjects. CPT induced a higher MPRI RPP also in women with coronary endothelial dysfunction, suggesting a greater contribution of the SNS to coronary flow than endothelial dysfunction. Further investigation in a larger cohort is needed., Competing Interests: Disclosure/Conflict of Interest Statement: The authors have nothing to disclose.

Background: Depression is an established predictor of coronary artery disease (CAD) progression and mortality. "Somatic" symptoms of depression such as fatigue and sleep impairment overlap with symptoms of CAD and independently predict CAD events. Differentiating between "somatic" and "cognitive" depressive symptoms in at-risk patients may improve our understanding of the relationship between depression and CAD., Methods: The study utilized data from the Women's Ischemia Syndrome Evaluation. Participants ( N = 641; mean age = 58.0 [11.4] years) were enrolled to evaluate chest pain or suspected myocardial ischemia. They completed a battery of symptom and psychological questionnaires (including the Beck Depression Inventory [BDI]) at baseline, along with quantitative coronary angiography and other CAD diagnostic procedures. The BDI provided scores for total depression and for cognitive and somatic depressive symptom subscales., Results: Two hundred and fourteen (33.4%) women met criteria for obstructive CAD. Logistic regression models were used to examine relationships between depression symptoms and obstructive CAD. Neither BDI total scores (odds ratio [OR] =1.02, 95% confidence interval [CI], 0.99-1.05, P = 0.053) nor BDI cognitive scores (OR = 1.02, 95% CI, 1.00-1.04, P = 0.15) predicted CAD status. BDI somatic symptom scores, however, significantly predicted CAD status and remained statistically significant after controlling for age, race, and education (OR = 1.06, 95% CI, 1.01-1.12, P = 0.02)., Conclusion: Among women with suspected myocardial ischemia, somatic but not cognitive depressive symptoms predicted an increased risk of obstructive CAD determined by coronary angiography. Consistent with prior reports, these results suggest a focus on somatic rather than cognitive depressive symptoms could offer additional diagnostic information., Competing Interests: Conflicts of interest There are no conflicts of interest.

Cardiovascular disease (CVD) prevalence remains elevated globally. We have previously shown that a one-week lifestyle "immersion program" leads to clinical improvements and sustained improvements in quality of life in moderate to high atherosclerotic CVD (ASCVD) risk individuals. In a subsequent year of this similarly modeled immersion program, we again collected markers of cardiovascular health and, additionally, evaluated intestinal microbiome composition. ASCVD risk volunteers ( n = 73) completed the one-week "immersion program" involving nutrition (100% plant-based foods), stress management education, and exercise. Anthropometric measurements and CVD risk factors were compared at baseline and post intervention. A subgroup ( n = 22) provided stool, which we analyzed with 16S rRNA sequencing. We assessed abundance changes within-person, correlated the abundance shifts with clinical changes, and inferred functional pathways using PICRUSt. Reductions in blood pressure, total cholesterol, and triglycerides, were observed without reduction in weight. Significant increases in butyrate producers were detected, including Lachnospiraceae and Oscillospirales . Within-person, significant shifts in relative abundance (RA) occurred, e.g., increased Lachnospiraceae (+58.8% RA, p = 0.0002), Ruminococcaceae (+82.1%, p = 0.0003), Faecalibacterium prausnitzii (+54.5%, p = 0.002), and diversification and richness. Microbiota changes significantly correlated with body mass index (BMI), blood pressure (BP), cholesterol, high-sensitivity C-reactive protein (hsCRP), glucose, and trimethylamine N-oxide (TMAO) changes. Pairwise decreases were inferred in microbial genes corresponding to cancer, metabolic disease, and amino acid metabolism. This brief lifestyle-based intervention improved lipids and BP and enhanced known butyrate producers, without significant weight loss. These results demonstrate a promising non-pharmacological preventative strategy for improving cardiovascular health.

Study Objective: Women with ischemia and no obstructive coronary artery disease (INOCA) are at increased risk for heart failure (HF) hospitalizations, which is predominantly HF with preserved ejection fraction (HFpEF). We aimed to identify predictors for the development of heart failure HF in a deeply phenotyped cohort of women with INOCA and long-term prospective follow-up., Design Setting and Participants: Women enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) were evaluated for baseline characteristics including clinical history, medications, physical exam, laboratory data and angiographic data. Using a multivariate Cox analysis, we assessed the association between baseline characteristics and the occurrence of HF hospitalizations in 493 women with evidence of ischemia but no obstructive coronary disease, no prior history of HF, and available follow-up data., Results: During a median follow-up of 6-years, 18 (3.7%) women were hospitalized for HF. Diabetes mellitus and tobacco use were associated with HF hospitalization. In a multivariate analysis adjusting for known HFpEF predictors including age, diabetes, hypertension, tobacco use, and statin use, novel predictive variables included higher resting heart rate, parity and IL-6 levels and lower coronary flow reserve (CFR) and poor functional status., Conclusions: There is a considerable incidence of HF hospitalization at longer term follow-up in women with INOCA. In addition to traditional risk factors, novel risk variables that independently predict HF hospitalization include multi-parity, high IL-6, low CFR, and poor functional status. These novel risk factors may be useful to understand mechanistic pathways and future treatment targets for prevention of HFpEF., Competing Interests: Dr. C. Noel Bairey Merz serves as Board of Director for iRhythm, fees paid through CSMC from Abbott Diagnostics and Sanofi. Dr. Janet Wei reports honoraria paid to CSMC from Abbott Diagnostics. Dr. Vera Bittner serves on the Advisory Board for Pfizer, is senior guest editor for Circulation and Editor in Chief of ACCSAP. Dr. Bittner also reports fees paid to UAB from Sanofi, Astra Zeneca, Dalcor, Esperion, Novartis and Amgen. This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the U.S. Department of Health and Human Services., (© 2021 The Authors.)

Standard cardiology practice often defers preventive strategies to primary care providers. We aimed to evaluate the effectiveness of a preventive cardiology clinic focused on lifestyle and nutrition counseling combined with guideline-directed medical therapy on reducing cardiovascular disease (CVD) risk. We queried the University of Florida-Health database for patients enrolled in the preventive cardiology clinic, and a general and interventional cardiology clinic from January 2016 to October 2019. Mean change in weight and blood cholesterol including LDL cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG) were compared in the three clinics in the initial cohort and stratified into primary and secondary prevention. A propensity score-matched analysis was done to adjust for CVD risk factors and statin use. Among a cohort of 239 patients, enrollment in the preventive clinic (n = 99) was associated with greater weight loss at 6 months compared to other clinics (n = 140) (mean -1.7 vs +0.1 kg, p 0.007). Preventive clinic was also associated with greater mean reduction in LDL-C (-24.8 vs -7.1 mg/dl, p 0.021), TC (-29.3 vs -2.0, p 0.003) and TG (-19.7 vs +13.3, p 0.002) at both initial and last follow-up (median time 6 and 16 months). The association with reduction in TG was observed in both primary and secondary prevention, but reduction in LDL-C and TC was only significant in secondary prevention. In a propensity-matched linear regression analysis, preventive clinic was independently associated with LDL-C reduction (b -14.7, r -0.3, p 0.038). A preventive cardiology clinic focused on patient education can be effective in reducing CVD risk., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background: Approximately half of all women with anginal symptoms and/or signs of ischemia and no obstructive coronary artery disease (INOCA) referred for coronary angiography have elevated risk for major adverse cardiac events (MACE), poor quality of life and resource consumption. Yet, guidelines focus on symptom management while clinical practice typically advocates only reassurance. Pilot studies of INOCA subjects suggest benefit with intensive medical therapy (IMT) that includes high-intensity statins and angiotensin converting enzyme inhibitors (ACE-I) or receptor blockers (ARB) to provide the rationale for a randomized pragmatic trial to limit MACE., Methods: The Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD is a multicenter, prospective, randomized, blinded outcome evaluation (PROBE design) of a pragmatic strategy of IMT vs usual care (UC) in 4,422 symptomatic women with INOCA (NCT03417388) in approximately 70 United States sites. The hypothesis is that IMT will reduce the primary outcome of first occurrence of MACE by 20% vs. UC at ∼2.5 year followup. Secondary outcomes include quality of life, time to return to "duty"/work, healthcare utilization, angina, cardiovascular death and individual primary outcome components over 3 years follow-up. The study utilizes web-based data capture, e-consents, single IRB and centralized pharmacy distribution of strategy medications directly to patients' homes to reduce site and patient burden. A biorepository will collect blood samples to assess potential mechanisms., Conclusions: The results of this trial will provide important data necessary to inform guidelines regarding how best to manage this growing and challenging population of women with INOCA., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Antihypertensive medication nonadherence is a prevalent issue but is very difficult to accurately assess. To clarify this problem among hypertensive patients attending a cardiovascular disease outpatient clinic, we utilized high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) to assess antihypertensive medication adherence and identify trends by sex and drug class., Methods: Serum was extracted from blood samples obtained from patients with either drug-controlled or drug resistant hypertension (RHTN) and analyzed via HPLC-MS for antihypertensive drugs which were categorized by drug class as beta blockers, aldosterone antagonists, diuretics, ACE inhibitor/ARBs, or calcium channel blockers. Clinic blood pressure (BP), sex, and prescription regimens were extracted from medical records at or near the time of blood collection. "Adherence" or "nonadherence" was determined by comparison of the patient's prescribed drug regimen and the presence/absence of prescribed drug(s) in their serum., Results: Among 76 patients (47 women; mean age 63; 53% white), nonadherence was confirmed in 29%. RHTN was more frequently identified in women than men (55% vs 38%) and nonadherence was higher in women than men (34% vs 21%). BP in those who were adherent to prescribed antihypertensive drugs was significantly lower than in those who were nonadherent (129/75 vs 145/83 mmHg, p  = 0.0015). Overall, ACE inhibitors/ARBs were associated with the least nonadherence. Among women, nonadherence was highest for aldosterone antagonists, whereas among men, nonadherence was highest for diuretics., Conclusion: We observed nonadherence was more frequent among older women in a cohort of HTN and RHTN patients with cardiovascular disease based on HPLC-MS confirmed drug levels., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that couple have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Hypertension is associated with gut bacterial dysbiosis and gut pathology in animal models and people. Butyrate-producing gut bacteria are decreased in hypertension. RNA-seq analysis of gut colonic organoids prepared from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats was used to test the hypothesis that impaired interactions between the gut microbiome and gut epithelium are involved and that these would be remediated with butyrate supplementation. Gene expressions in immune responses including antigen presentation and antiviral pathways were decreased in the gut epithelium of the SHR in organoids and confirmed in vivo; these deficits were corrected by butyrate supplementation. Deficits in gene expression driving epithelial proliferation and differentiation were also observed in SHR. These findings highlight the importance of aligned interactions of the gut microbiome and gut immune responses to blood pressure homeostasis.

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., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy., Methods: Using an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis., Results: A total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922])., Conclusions: In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.)., (Copyright © 2021 Massachusetts Medical Society.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Knowledge of cardiovascular adaptations in athletes has predominantly focused on males, with limited data available on females who compromise a substantial percentage of all collegiate athletes. A multicenter retrospective cohort review of preparticipation cardiovascular screening data of 329 National Collegiate Athletic Association Division I female athletes was performed. This included physical exams, electrocardiograms, and echocardiograms. Female athletes in class IB sports had elevated systolic blood pressure (p = 0.01). For electrocardiograms, 7 (2%) had abnormal findings: 100% were white; 6 of 7 (86%) participated in IIC sports. Black athletes had longer PR intervals (p ≤ 0.001), whereas white athletes had longer QTc and QRS durations (p = 0.02 and 0.01, respectively). Athletes in IC and IIC sports had longer QTc intervals (p = 0.01). For echocardiographic parameters, no differences were noted based on race. However, significant differences were noted based on classification of sport: athletes in class IC sports had higher left-atrial volume indexes and E/A ratios. Athletes in class IB and IIC had increased left-ventricular wall thicknesses and aortic root dimensions. In conclusion, among one of the largest cohorts of collegiate female athlete preparticipation cardiac screening data to date, significant differences in various parameters based on classification of sport and race were observed. These categorizations should be considered when interpreting cardiovascular screening in female collegiate athletes to improve screening and guide future research., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To determine the relationship between coronary vascular dysfunction and history of migraines in women with suspected ischemia and no obstructive coronary arteries (INOCA)., Methods: In the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study, 402 women with suspected INOCA answered baseline angina questionnaires, including the Seattle Angina Questionnaire (SAQ). Coronary function testing (CFT) performed in a subgroup of 252 women evaluated for nonendothelial and endothelial-dependent coronary vascular function. Wilcoxon rank sum test, t -test, and linear regression models were performed., Results: Of the 252 women who underwent CFT, 126 (50%) women reported migraine history. Compared to women who reported no migraines, women with migraines were younger and more were premenopausal. They had more angina at rest, with strong emotions, and hot/cold temperatures, as well as angina that wakes them from sleep ( P < 0.05 for all). Women with migraines also scored worse on SAQ angina frequency and quality of life P < 0.01 for both). There was no difference in prevalence of coronary vascular dysfunction in the two groups. In addition, linear regression models demonstrated no significant age-adjusted differences in absolute CFT variables., Conclusion: Among women with suspected INOCA, migraine history is prevalent and women with migraines have worse angina compared to those without migraines. Coronary vascular dysfunction diagnosed by CFT does not appear to relate to migraine history., Competing Interests: Conflicts of interest All authors declared that there are no conflicts of interest.

Background Sexual minority, or lesbian, gay, and bisexual (LGB), individuals are at increased risk for cardiovascular disease attributable to elevated rates of health risk factors. However, although there is clear evidence that statin use can prevent cardiovscular disease in certain adult populations, no studies have examined how statins are being used among the LGB population. This study aimed to examine the prevalence and predictors of statin use among LGB and non-LGB individuals using Facebook-delivered online surveys. Methods and Results We conducted a cross-sectional online survey about statin use in adults ≥40 years of age between September and December 2019 using Facebook advertising (n=1531). We calculated the prevalence of statin use by age, sexual orientation, and statin benefit populations. We used multivariable logistic regression to examine whether statin use differed by sexual orientation, adjusting for covariates. We observed a significantly lower rate of statin use in the LGB versus non-LGB respondents (20.8% versus 43.8%; P <0.001) in the primary prevention population. However, the prevalence of statin use was not statistically different in the LGB versus non-LGB respondents in the secondary prevention population. Adjusting for the covariates, the LGB participants were less likely to use statins than the non-LGB respondents in the primary prevention population (odds ratio, 0.37; 95% CI, 0.19-0.70). Conclusions Our results are the first to emphasize the urgent need for tailored, evidence-based cardiovascular disease prevention programs that aim to promote statin use, and thus healthy aging, in the LGB population.

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.

Recent clinical guidelines recommend lower blood pressure (BP) goals for most patients, and recent trends have favored use of automated unattended BP measurements in the office setting to minimize observer error and white-coat effects. Patients attending a routinely scheduled CVD clinic visit were prospectively randomized to BP measured using an attended, followed by an unattended method, or vice versa, after a controlled rest period. All study BP measurements were obtained in triplicate using the automated Omron HEM-907XL BP monitor, and averaged. The outcome was difference in SBP. Routinely measured clinic BP from the same visit was extracted from the medical record, and compared with attended and unattended BP. A total of 102 patients were randomized, and mean age was 63 years, 52% female and 75% Caucasian. Attended and unattended SBP was 125.4 ± 20.4 and 122.6 ± 21.0 mm Hg, mean ± SD, respectively. Routine clinic SBP was 130.6 ± 23.6 mm Hg. Attended SBP was 2.7 mm Hg higher than the unattended measurement (95% CI 1.3-4.1; P = .0002). Routine clinic SBP was 5.2 mm Hg higher than attended SBP (95% CI 2.4-8.0; P = .0003) and 8.0 mm Hg higher than unattended SBP (95% CI 5.4-10.5; P < .0001). Attended measurement of BP is significantly higher than unattended measurement and the difference is physiologically meaningful, even in a CVD cohort with generally well-controlled hypertension. Furthermore, routine clinic SBP substantially overestimates both attended and unattended automated SBP, with important implications for treatment decisions like dose and/or drug escalation., (© 2020 Wiley Periodicals LLC.)

Background: Hypertension and coronary artery disease (CAD) are a prevalent combination in older women, however limited data are available to guide blood pressure (BP) management. We hypothesized that older women with hypertension and CAD may not derive long-term benefit by achieving systolic BP (SBP) < 130 mmHg., Methods: We analyzed long-term all-cause mortality data from the International Verapamil SR/Trandolapril Study (INVEST), stratified by risk attributable to clinical severity of CAD (women with prior coronary events of myocardial infarction or revascularization considered high risk, all others at low risk) and by age group (50-64 or ≥65 years). The prognostic impact of achieving mean in-trial SBP <130 (referent group) was compared with 130-139 and ≥ 140 mmHg using Cox proportional hazards, adjusting for demographic and clinical characteristics., Results: SBPs <130, 130-139, and ≥140 were achieved in 2960, 3024, and 3232 women, respectively. Among high-risk women aged ≥65 years, those achieving SBP 130-139 mmHg had lower mortality up to 16.7 years later than those with SBP <130 (hazard ratio [HR] 0.81, 95% CI 0.69-0.96). High-risk women aged 50-64 achieving SBP 130-139 had a similar mortality risk as those with SBP <130 (HR 1.21, 95% CI 0.87-1.68), while those achieving SBP ≥140 mmHg had a higher mortality risk than SBP < 130 (HR 1.92, 95% CI 1.37-2.68). A similar pattern was observed among low-risk women ≥65 and <65 years old., Conclusion: Among women ≥65 years old with hypertension and prior coronary events, in-trial SBP between 130 and 139 mmHg was associated with lower mortality over the long term versus SBP <130 mmHg., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Authors.)

This paper evaluated cross-sectional relationships between psychological stress and coronary artery disease (CAD) risk among women with suspected ischaemia and no obstructive coronary artery disease (INOCA). Between 1996 and 2000, 551 women with INOCA were enrolled in the Women's Ischemia Syndrome Evaluation (WISE) cohort from four U.S. institutions. Between 2009 and 2012, 376 women with INOCA were recruited from two U.S. institutions for an independent cohort study titled WISE-Coronary Vascular Dysfunction (WISE-CVD). Participants underwent coronary angiography and testing for CAD symptoms and risk factors at baseline. Psychological stress was assessed in the form of home/work stress in WISE and home/work stress and financial stress in WISE-CVD. Results showed that home/work stress predicted greater depression, functional impairment, CAD symptoms, and lower self-rated health in WISE but was inconsistent as a predictor in WISE-CVD. In contrast, >60% of WISE-CVD women reported moderate or severe financial stress. Financial stress levels predicted more CAD risk factors and cardiac symptoms, poorer self-rated health, and greater depression and functional impairment. Among women with INOCA, psychological stress was associated with CAD symptoms and CAD risk factors. The prevalence and predictive value of psychological stress in this population supports the inclusion of stress measures in future CAD research., (© 2020 John Wiley & Sons, Ltd.)

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.

Background: Women with evidence of ischemia and no obstructive coronary arteries (INOCA) often have coronary microvascular dysfunction (CMD) indicated by impaired coronary flow reserve (CFR) to adenosine. Low CFR is associated with an adverse prognosis, including incident heart failure. Because the CFR calculation relies on the baseline intrinsic coronary vasomotor flow velocity, a major determinate of CFR and the degree of variation in baseline flow alone may be an important contributor to risk of adverse outcomes in women with CMD. A better understanding of baseline blood flow in the setting of low CFR and its association with myocardial performance would be helpful., Methods: We evaluated 74 women who underwent invasive coronary reactivity testing in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study and had impaired CFR (<2.32). We assessed the relationship between coronary artery baseline average peak velocity (bAPV) at rest and cardiac magnetic resonance imaging measures of left ventricular (LV) structure and function., Results: When stratified as low (<22 cm/s) versus high (≥22 cm/s) bAPV, there were no differences in cardiovascular risk factors, coronary plaque burden, or LV structure. However, low bAPV was associated with higher LV end-diastolic filling pressure (P = 0.04), lower LV ejection fraction (P = 0.001), and differences in late systolic and diastolic strain rates (P = 0.01 to 0.05)., Conclusions: In women with impaired CFR, low resting coronary flow velocity is associated with more adverse myocardial performance, which may contribute to risk for adverse outcomes and particularly heart failure in women with CMD., Competing Interests: Declaration of competing interest Dr. Bairey Merz has received personal fees paid through CSMC from Abbott Diagnostics, Sanofi and serves as Board of Director at iRhythm. Dr. Pepine has received research grants from GE Healthcare, Merck, Sanofi, CLS Behring, Biocardia, McJunkin Family Foundation, Brigham & Women's Hospital, Gatorade Trust through the University of Florida Department of Medicine, Athersys Inc., AMI MultiStem, and Mesoblast, Inc.; has received consultant fees/honoraria from Verily Life Sciences LLC Project Baseline OSMB (Google), Ironwood, XyloCor, Slack Inc., Imbria Pharmaceuticals, Milestone Pharmaceuticals Inc., Ventrix, Inc., AstraZeneca Pharmaceuticals, and Sanofi-Aventis. Dr. Handberg receives research grants from Aastrom Biosciences, Amorcyte, Biocardia, Brigham and Women's Hospital, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Duke Clinical Research Institute, East Carolina University, Everyfit Inc., Medtronic, Merck & Co., Mesoblast, National Institutes of Health (NIH), NIH through University of Rochester, NIH through Brigham and Women's Health, NIH through University of Texas, PCORI, and Sanofi Aventis; Research grant and educational grant from Gilead Sciences; Unrestricted educational grants for the Vascular Biology Working Group from Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Ionis, and Relypsa; and Consultant fees from Bristol-Myers Squibb Company., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: We assessed history of adverse pregnancy outcomes (APOs) and coronary microvascular dysfunction (CMD) in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) cohort of women with signs and symptoms of ischemia without obstructive coronary artery disease (CAD). We hypothesized that women with CMD with symptoms and signs of ischemia, without obstructive CAD, are more likely to have a history of APO. Materials and Methods: WISE-CVD recruited women with suspected ischemia found to have no obstructive CAD ( n  = 324). A subset of these women underwent coronary reactivity testing, including coronary flow reserve (CFR) ( n  = 185). Relationship between history of any APO and CMD was assessed by multivariable linear regression analyses. APOs included any of the following: hypertension during pregnancy, preeclampsia, eclampsia, gestational diabetes, or intrauterine growth restriction (low-birth-weight child). Results: Overall, 79/324 (24%) women reported at least one APO. Women with APOs were younger (52 vs. 56 years, p  = 0.001), were more likely obese (body mass index 32 vs. 29 kg/m 2 , p  = 0.004), and had a history of hypertension (56% vs 36%, p  = 0.002), but otherwise had no additional differences in cardiac risk variables versus women without APOs. Among the subgroup who underwent invasive CFR testing ( n  = 185), those with an APO had lower CFR (2.53 vs. 2.76, p  = 0.016) versus those without APO. Conclusions: History of APOs in women with signs and symptoms of ischemia without obstructive CAD is associated with lower CFR indicative of CMD. Whether common pathways involving diffuse microvascular dysfunction may account for this suggested association remains unclear. Further investigation is needed to expand on these exploratory findings.

Background: Hypertension is a major modifiable risk factor for coronary artery disease (CAD), the main cause of death in women. While association between the two is frequent, limited data exist regarding the feasibility of blood pressure (BP) management and outcomes in women across the spectrum of CAD. Accordingly, we analyzed patient characteristics, BP control rates, and outcomes among hypertensive women with CAD, enrolled in The INternational VErapamil SR-trandolapril STudy (INVEST). Methods: The 11,770 hypertensive women with CAD in INVEST were studied based on presence ( n  = 3,879) or absence ( n  = 7,891) of history of myocardial infarction (MI) or coronary revascularization, to evaluate outcomes across risk groups based on severity of CAD. Results: Women with prior MI or revascularization were older (4 years, p  < 0.0001), were predominantly white (62% vs. 29%), and had more associated comorbidities than women without these events. At 24 months, JNC VI (sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) BP control rates were lower in women with prior MI or revascularization (57% vs. 64%, p  < 0.0001), despite more intensive antihypertensive therapy. The primary outcome (first occurrence of all-cause death, nonfatal MI, or nonfatal stroke) was also more frequent in women with prior MI or revascularization (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.34-1.74), who were 42% more likely to die (adjusted HR 1.42; 95% CI 1.22-1.64), twice as likely to have a nonfatal MI (adjusted HR 2.4, 95% CI 1.64-3.51), and 56% more likely to have a nonfatal stroke (adjusted HR 1.56, 95% CI 1.1-2.21). Conclusions: In a prospective, multinational cohort of hypertensive women with CAD, those with prior MI or revascularization comprised a group at higher risk for death, nonfatal MI, and nonfatal stroke, and were less likely to have their BP controlled, despite more aggressive therapy. The feasibility and benefit of reducing BP to <130/80 mmHg in women, particularly with more severe CAD, warrant further investigation.

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± 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Today is an age of rapid digital integration, yet the capabilities of modern-day smartphones and smartwatches are underappreciated in daily clinical practice. Smartphones are ubiquitous, and smartwatches are very common and on the rise. This creates a wealth of information simply waiting to be accessed, studied and applied clinically, ranging from activity level to various heart rate metrics. This review considers commonly used devices, the validity and accuracy of the data they obtain and potential clinical application of the data., Competing Interests: Disclosure: The authors have no conflicts of interest to disclose., (Copyright © 2019, Radcliffe Cardiology.)

Objective: In a separate, contemporary cohort, we sought to confirm findings of the original Women's Ischemia Syndrome Evaluation (WISE)., Background: The original WISE observed a high prevalence of both invasively determined coronary endothelial and coronary microvascular dysfunction (CMD) that predicted adverse events in follow-up., Methods: We comparatively studied the WISE-Coronary Vascular Dysfunction (CVD) cohort (2009-2011), with signs and symptoms of ischemia but without significant CAD, to the original WISE (1997-2001) cohort. CMD was defined as coronary flow reserve (CFR) ≤2.5, or endothelial dysfunction as epicardial coronary artery constriction to acetylcholine (ACH), or <20% epicardial coronary dilation to nitroglycerin (NTG)., Results: In WISE (n=181) and WISE-CVD (n=235) women, mean age in both was 54 years, and 83% were white (WISE) vs 74% (WISE-CVD, p=0.04). Use of hormone replacement therapy was less frequent in WISE-CVD vs WISE (46% vs 57%, p=0.026) as was presence of hypertension (40% vs 52%, p=0.013), hyperlipidemia (20% vs 46%, p<0.0001), and smoking (46% vs 56%, p=0.036). Similar rates were observed in WISE-CVD and WISE cohorts for CMD (mean CFR 2.7±0.6 vs 2.6±0.8, p=0.35), mean change in diameter with intracoronary ACH (0.2±10.0 vs 1.6±12.8 mm, p=0.34), and mean change in diameter with intracoronary NTG (9.7±13.0 vs 9.8±13.5 mm, p=0.94), respectively., Conclusions: This study confirms prevalence of CMD in the contemporary WISE-CVD cohort similar to that of the original WISE cohort, despite a lower risk factor burden in WISE-CVD. Because these coronary functional abnormalities predict major adverse cardiac events, clinical trials of therapies targeting these abnormalities are indicated., Competing Interests: There are no relevant conflicts of interest of any of the authors to disclose., (Copyright © 2019 R. David Anderson et al.)

This pilot randomized controlled trial (RCT) was designed to provide the preliminary data necessary to conduct a full-scale trial to compare the efficacy of differing first-line antihypertensive medications in improving functional status in older adults, when combined with exercise. The primary objectives were to assess study feasibility, safety, and protocol integrity. Dependent outcomes included gait speed, exercise capacity, body composition, and systemic cardiometabolic biomarkers. Thirty-one physically inactive older adults (70.6 ± 6.1 years) with hypertension and functional limitations were randomly assigned to 1) Perindopril (8 mg/day n = 10), 2) Losartan (100 mg/day; n = 13), or 3) Hydrochlorothiazide (HCTZ: 25 mg/day; n = 8). Participants were also assigned to a 24-week multimodal exercise intervention, separated into an aerobic and concurrent (aerobic + resistance) phase to evaluate potential mode effects. Retention was 84% (26/31), and compliance was >90% and >79% with medication and exercise, respectively. A total of 29 adverse events (Perindopril = 5; Losartan = 12; HCTZ = 11) and one unrelated serious adverse event were observed throughout the trial. Overall, this pilot RCT provided critical data and identified several challenges to ultimately designing and implementing a fully powered trial., Competing Interests: The authors declare no conflicts of interest

Background: In a prior trial of late sodium channel inhibition (ranolazine) among symptomatic subjects without obstructive coronary artery disease (CAD) and limited myocardial perfusion reserve index (MPRI), we observed no improvement in angina or MPRI, overall. Here we describe the clinical characteristics and myocardial perfusion responses of a pre-defined subgroup who had coronary flow reserve (CFR) assessed invasively., Methods: Symptomatic patients without obstructive CAD and limited MPRI in a randomized, double-blind, crossover trial of ranolazine vs. placebo were subjects of this prespecified substudy. Because we had previously observed that adverse outcomes and beneficial treatment responses occurred in those with lower CFR, patients were subgrouped by CFR <2.5 vs ≥2.5. Symptoms were assessed using the Seattle Angina Questionnaire and the SAQ-7, and left-ventricular volume and MPRI were assessed by magnetic resonance imaging (MRI). Coronary angiograms, CFR, and MRI data were analyzed by core labs masked to treatment and patient characteristics., Results: During qualifying coronary angiography, 81 patients (mean age 55 years, 98% women) had invasively determined CFR 2.69 ± 0.65 (mean ± SD; range 1.4-5.5); 43% (n = 35) had CFR <2.5. Demographic and symptomatic findings did not differ comparing CFR subgroups. Those with low CFR had improved angina (p = 0.04) and midventricular MPRI (p = 0.03) with ranolazine vs placebo. Among patients with low CFR, reduced left-ventricular end-diastolic volume predicted a beneficial angina response., Conclusions: Symptomatic patients with CFR <2.5 and no obstructive CAD had improved angina and myocardial perfusion with ranolazine, supporting the hypothesis that the late sodium channel is important in management of coronary microvascular dysfunction., Trial Registration: clinicaltrials.gov Identifier NCT01342029., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aging and diabetes are associated with decreased aerobic fitness, an independent predictor of mortality. Aerobic exercise is prescribed to improve aerobic fitness; however, middle-aged/older diabetic patients often suffer from mobility limitations which restrict walking. Non-weight-bearing/low-impact exercise is recommended but the optimal exercise prescription is uncertain. The goal of this randomized controlled trial was twofold: 1) to test if high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), implemented on a non-weight-bearing all-extremity ergometer, are feasible, well-tolerated and safe in middle-aged/older adults with type 2 diabetes; and 2) to test whether all-extremity HIIT is more effective in improving aerobic fitness than MICT. A total of 58 sedentary individuals with type 2 diabetes (46 to 78 years; 63 ± 1) were randomized to all-extremity HIIT (n = 23), MICT (n = 19) or non-exercise control (CONT; n = 16). All-extremity HIIT and MICT, performed 4×/week for 8 weeks under supervision, resulted in no adverse events requiring hospitalization or medical treatment. Aerobic fitness (VO 2peak ) improved by 10% in HIIT and 8% in MICT and maximal exercise tolerance increased by 1.8 and 1.3 min, respectively (P ≤ 0.002 vs. baseline; P ≥ 0.9 for HIIT vs. MICT). In conclusion, all-extremity HIIT and MICT are feasible, well-tolerated and safe and result in similar improvements in aerobic fitness in middle-aged/older individuals with type 2 diabetes. These findings have important implications for exercise prescription for diabetic patients; they indicate that all-extremity exercise is a feasible alternative to weight-bearing exercise and those who are unable or unwilling to engage in HIIT may receive similar benefits from MICT., (Copyright © 2018 Elsevier Inc. All rights reserved.)