Merz, C. Noel Bairey

Abstract OBJECTIVES This study describes coronary revascularization strategies used by sex and age in the USA. METHODS A sex-stratified cohort study from the National Inpatient Sample from the Agency for Healthcare Research and Quality (USA) including patients admitted for coronary revascularization with primary or secondary diagnoses of chronic coronary syndrome or non-ST elevation myocardial infarction who underwent ≥3-vessel coronary artery bypass grafting or percutaneous coronary intervention from January 2019 to December 2020. The primary outcome was the use rate of coronary artery bypass grafting or multivessel percutaneous coronary intervention. Prespecified subgroups included age and non-ST elevation myocardial infarction. RESULTS Among 121 150 patients (21.7% women), there were no sex differences in age (women: 66.6 [66.5–66.7], men: 67.6 [67.5–67.7], standardized mean difference: 0.1) or non-ST elevation myocardial infarction incidence (women: 37.4%, men: 45.7%, standardized mean difference: 0.17). The majority of women (74.2%) and men (84.9%) underwent bypass grafting, which was unaffected by age, race or non-ST elevation myocardial infarction. Women were less likely to undergo bypass grafting than percutaneous intervention (adjusted odds ratio 0.49, 95% confidence interval 0.44–0.54; P < 0.001) and a disparity most pronounced in patients >80 years old (adjusted odds ratio 0.31, 95% confidence interval 0.22–0.45; P < 0.001). CONCLUSIONS Most patients with multivessel coronary artery disease needing revascularization undergo bypass grafting, irrespective of sex, age or clinical presentation. The sex disparity in the use of bypass grafting is mostly seen among patients >80 years old.

Background: Proprotein convertase subtisilin/kexin 9 (PCSK9) raises low-density lipoprotein cholesterol (LDL-C) levels and is associated with inflammation, which is elevated in HIV and hepatitis C virus (HCV) infection. We compared PCSK9 levels in people with co-occurring HIV and HCV (HIV/HCV) vs. HIV alone, and evaluated the impact of HCV direct-acting antiviral (DAA) therapy on PCSK9. Design: A prospective, observational cohort study. Methods: Thirty-five adults with HIV/HCV and 37 with HIV alone were evaluated, all with HIV virologic suppression and without documented cardiovascular disease. Circulating PCSK9 and inflammatory biomarkers were measured at baseline and following HCV treatment or at week 52 (for HIV alone) and compared using Wilcoxon tests and Spearman correlations. Results: At baseline, PCSK9 trended higher in HIV/HCV vs. HIV alone (307 vs. 284 ng/ml, P = 0.06). Twenty-nine participants with HIV/HCV completed DAA therapy with sustained virologic response. PCSK9 declined from baseline to posttreatment 1 (median 7.3 weeks after end of therapy [EOT]) and posttreatment 2 (median 43.5 weeks after EOT), reaching levels similar to HIV alone; median within-person reduction was -60.5 ng/ml (P = 0.003) and -55.6 ng/ml (P = 0.02), respectively. Decline in PCSK9 correlated with decline in soluble (s)E-selectin and sCD163 (r = 0.64, P = 0.002; r = 0.58, P = 0.008, respectively), but not with changes in LDL-C or other biomarkers. No significant change in PCSK9 occurred in the HIV alone group over 52 weeks. Conclusion: PCSK9 declined with DAA therapy in participants with HIV/HCV, correlating with declines in several inflammatory biomarkers but not LDL-C. Elevated PCSK9 with HCV may be linked to particular HCV-associated inflammatory pathways more so than cholesterol homeostasis.

Abstract Context Endothelial dysfunction is a preclinical cardiovascular disease (CVD) marker. Due to various neuroendocrine aberrations, functional hypothalamic amenorrhea (FHA) may be a sex-specific risk factor for CVD in young women. Objective To investigate endothelial function in women with FHA, compared with eumenorrheic controls and recently menopausal women. Methods We performed a cross-sectional analysis among women with FHA (n = 30), eumenorrheic controls (n = 29), and recently menopausal women (n = 30). FHA was defined as amenorrhea ≥3 consecutive months, estradiol <50 pg/mL, follicle-stimulating hormone (FSH) < 10 mIU/mL, and luteinizing hormone (LH) < 10 mIU/mL, excluding other etiologies. Participants were recruited through obstetrics and gynecology referrals, social media advertising, and review of electronic health records. Preclinical CVD was measured using EndoPAT 2000 to calculate reactive hyperemic index (RHI). RHI ≤1.67 indicates endothelial dysfunction. Results Mean estradiol levels in women with FHA, as compared with eumenorrheic controls and recently menopausal women, were 29.0 ± 18.1, 46.4 ± 15.7, and 10.9 ± 14.4 pg/mL (P < .0001), respectively. Women with FHA had lower insulin (P = .0095) and higher cortisol (P = .0004) compared with controls. RHI was significantly lower in women with FHA compared with eumenorrheic controls and recently menopausal women (1.8 ± 0.5 vs 2.2 ± 0.5 vs 2.2 ± 0.6, respectively; P = .008), and 35% of women with FHA had RHI ≤1.67, consistent with endothelial dysfunction. Conclusion These results demonstrate endothelial dysfunction in 1 out of 3 young women with FHA. FHA may be a contributor to preclinical CVD, and it is not explained by hypoestrogenemia alone.

Introduction: Hypothalamic amenorrhea (HA) is a neuroendocrine disorder characterized by ovulatory dysfunction, anovulation, and infertility, which can be prolonged for months to years. Menstrual cycle irregularity and amenorrhea identify individuals with higher CVD risk, but existing evidence has not examined HA separately from polycystic ovary syndrome (PCOS). It remains unknown whether HA is associated with CVD events across the lifecourse. Hypothesis: We hypothesized that the HA phenotype (oligo/amenorrhea without PCOS traits) would identify individuals at increased risk for CVD. Methods: Nurses’ Health Study II participants with available information on menstrual cycle characteristics who were premenopausal and free of CVD at baseline comprised the analytic sample (n=83,281). Menstrual cycle regularity was retrospectively reported for ages 18-22y on the baseline questionnaire in 1989 while the 1993 biennial questionnaire captured current menstrual cycle regularity (at ages 29-49y); PCOS traits (severe acne, hirsutism) were additionally ascertained in 1993. Participants were followed for confirmed incident CVD (MI, stroke, and fatal CHD) from 1993 through 2017. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the relationship between HA and CVD, adjusted for age, race/ethnicity, parental education, parental history of CVD <60y, and behavioral risk factors (smoking, physical activity, diet, alcohol intake, body mass index). Results: Thirteen percent of participants (n=11,071) ever had HA: 8.5% of participants (n=7,081) had HA at ages 18-22y while 6.5% (n=5,428) had HA at ages 29-46y. Persistent HA (HA at both 18-22y and 29-46 y) was identified in 1.7% of participants (n=1,438). CVD events occurred in 253 individuals who ever had HA (HA at either 18-22y or 29-46y) and 1,228 individuals without the HA phenotype. Individuals who ever had HA had a 20% higher rate of CVD (CI: 1.05-1.38). HA phenotype at ages 18-22y was not associated with CVD risk (HR=1.14; CI: 0.96-1.35) while HA phenotype at ages 29-46y was associated with a 30% higher rate of CVD (CI: 1.10-1.54) compared to individuals without HA phenotype. Individuals with persistent HA across both age ranges had a 69% higher rate of CVD (CI: 1.24-2.28). Underlying associations were strongest between ever HA and stroke (HR=1.25; CI: 1.03-1.51) and between persistent HA and CHD (HR=1.90; CI: 1.27-2.86), although case counts were small. Conclusions: HA phenotype in mid-adulthood identified individuals at increased risk of CVD compared to those without HA. As there are multiple HA subtypes, defined by varying combinations of psychosocial stress, anxiety, physical activity and weight loss, future studies should examine which HA subtypes are associated with CVD risk.

Cardiovascular (CV) disease (CVD) is the major health burden and cause of death for women. Marked disparities exist in CVD diagnosis, prevention, and treatment between women and men – as well as lack of female-specific data. Population, physiologic, translational, and clinical trial studies of sex and gender differences in CVD [[Unable to Display Character: &#8211;]] even when only women are studied[[Unable to Display Character: &#8211;]] often do not collect relevant data specific to women that could inform study outcomes. The ISIS CVD Network of the Society for Women’s Health Research compiled an inventory of items specific for women across the lifespan, together with references for methods and strategies to gather and evaluate this information; some items comprise robust measures, others are in development. The objective is to enhance usefulness of CVD research data in understanding sex and gender differences, thereby optimizing healthcare delivery and outcomes for women. Included are hormonal variables (menstrual cycle phase, hormone levels) oral contraceptive use, pregnancy history/complications, polycystic ovary syndrome (PCOS) components, measures of menopause, and menopausal hormone therapy, variables generally not collected in research studies, but essential to determine their role as sex-specific contributors to CV health and disease. Clear associations exist between reproductive health and CV health and disease. For example 25-33% of women experience complications of pregnancy that may precede and predispose to CVD. Vascular complications during pregnancy, antecedent risk factors and subsequent clinical CVD can be ascertained using medical records, birth registries, and/or maternal recall. Evaluating compilations of patient data with known hormonal or menopausal status using reference standards and patient data for PCOS could inform relationships to subsequent CV outcomes. Variables predominant among women that preferentially disadvantage them should be considered; e.g. psychosocial issues and elderly age. Depressive disorders are twice as common among women as men. They adversely affect CVD outcomes in women, yet the effect of reproductive life cycle and of hormonal fluctuations on depression and etiologic contributions of depression to CVD are inadequately explored. In addition to traditional CVD risk factors, diabetes mellitus, chronic inflammatory disorders, oxidative stress, vasomotor dysfunction, coronary microvascular disorders, and other novel risk variables that preferentially impact women should be explored. Along with increased enrollment of women in CVD research studies and analysis of clinical and genetic studies by sex, improvements and expansion of study design must include these understudied uniquely or predominantly female characteristics. This will enhance the quality and quantity of evidence-based medicine to guide CVD care in women and men thereby setting the stage for personalized approach to medicine.

Background: Coronary microvascular dysfunction results in angina and adverse outcomes in patients with evidence of ischemia and nonobstructive coronary artery disease; however, no specific therapy exists. CD34+ cell therapy increases microvasculature in preclinical models and improves symptoms, exercise tolerance, and mortality in refractory angina patients with obstructive coronary artery disease. The objective of this research was to evaluate the safety, tolerability, and efficacy of intracoronary CD34+ cell therapy in patients with coronary microvascular dysfunction. Methods: We conducted a 2-center, 20-participant trial of autologous CD34+ cell therapy (protocol CLBS16-P01; NCT03508609) in patients with ischemia and nonobstructive coronary artery disease with persistent angina and coronary flow reserve ≤2.5. Efficacy measures included coronary flow reserve, angina frequency, Canadian Cardiovascular Society angina class, Seattle Angina Questionnaire, SF-36, and modified Bruce exercise treadmill test obtained at baseline and 6 months after treatment. Autologous CD34+ cells (CLBS16) were mobilized by administration of granulocyte-colony stimulating factor 5µg/kg/day for 5 days and collected by leukapheresis. Participants received a single intracoronary left anterior descending infusion of isolated CD34+ cells in medium that enhances cell function. Results: Coronary flow reserve improved from 2.08±0.32 at baseline to 2.68±0.79 at 6 months after treatment ( P <0.005). Angina frequency decreased ( P <0.004), Canadian Cardiovascular Society class improved ( P <0.001), and quality of life improved as assessed by the Seattle Angina Questionnaire ( P ≤0.03, all scales) and SF-36 ( P ≤0.04, all scales). There were no cell-related serious adverse events. Conclusions: In this pilot clinical trial of microvascular angina, patients with ischemia and nonobstructive coronary artery disease receiving intracoronary infusion of CD34+ cell therapy had higher coronary flow reserve, less severe angina, and better quality of life at 6 months. The current study supports a potential therapeutic role for CD34+ cells in patients with microvascular angina. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03508609.

Cardiovascular disease continues to be the leading cause of death among women in the United States, accounting for ≈1 of every 3 female deaths. Sex-specific data focused on cardiovascular disease have been increasing steadily, yet is not routinely collected nor translated into practice. This comprehensive review focuses on novel and unique aspects of cardiovascular health in women and sex differences as they relate to clinical practice in the prevention, diagnosis, and treatment of cardiovascular disease. This review also provides current approaches to the evaluation and treatment of acute coronary syndromes that are more prevalent in women, including myocardial infarction associated with nonobstructive coronary arteries, spontaneous coronary artery dissection, and stress-induced cardiomyopathy (Takotsubo Syndrome). Other cardiovascular disease entities with higher prevalence or unique considerations in women, such as heart failure with preserved ejection fraction, peripheral arterial disease, and abdominal aortic aneurysms, are also briefly reviewed. Finally, recommendations for cardiac rehabilitation are addressed.

Nonobstructive coronary artery disease (CAD) in women is associated with adverse cardiovascular (CV) outcomes; however, information regarding genetic variants that predispose women to nonobstructive CAD is lacking. Women from the Women's Ischemia Syndrome Evaluation (WISE) Study and the St. James Women Take Heart (WTH) Study were genotyped with the Cardio-MetaboChip. WISE enrolled women with symptoms and signs of ischemia referred for coronary angiography; WTH enrolled asymptomatic, community-based women without heart disease. Analyses were conducted with a case (WISE) - control (WTH) design and multivariate logistic regression models to investigate genetic variation associated with likelihood of nonobstructive CAD. One genetic marker, single nucleotide polymorphism (SNP) rs2301753 on chromosome 6 in RNF39, achieved chip-wide significance for nonobstructive CAD ( P < 9.5 × 10−7). After adjusting for baseline characteristics, we found no variants achieved chip-wide significance. However, SNP rs2301753 on chromosome 6 in RNF39 was associated with reduced likelihood of nonobstructive CAD [odds ratio (OR) 0.42 and 95% confidence interval (CI) of 0.29 to 0.68], at a nominal level of P = 5.6 × 10−6, while SNP rs12818945 in the ATP2B1 locus on chromosome 12 was associated with increased odds for nonobstructive CAD (OR 2.38 and 95% CI of 1.63 to 3.45) and nominal P = 5.8 × 10−6. The functions of RNF39 and ATP2B1 raise the possibility that genes involved in cardio-dysfunction may contribute to nonobstructive CAD in Caucasian women and may provide insights into novel approaches for therapy and prevention. If replicated, incorporation of these genetic variants into diagnostic evaluation may identify women at high risk for nonobstructive CAD.