Sex-specific differences in cardiovascular risk factors and implications for cardiovascular disease prevention in women.

Cardiovascular disease (CVD) is the leading cause of mortality for women globally. Sex differences exist in the relative risks conferred by traditional CVD risk factors, including diabetes, hypertension, obesity, and smoking. Additionally, there are female-specific risk factors, including age of menarche and menopause, polycystic ovary syndrome, infertility and the use of assisted reproductive technology, spontaneous pregnancy loss, parity, and adverse pregnancy outcomes, as well as female-predominant conditions such as autoimmune diseases, migraines, and depression, that enhance women's cardiovascular risk across the lifespan. Along with measurement of traditional risk factors, these female-specific factors should also be ascertained as a part of cardiovascular risk assessment to allow for a more comprehensive overview of the risk for developing cardiometabolic disorders and CVD. When present, these factors can identify women at elevated cardiovascular risk, who may benefit from more intensive preventive interventions, including lifestyle changes and/or pharmacotherapy such as statins. This review describes sex differences in traditional risk factors and female-specific/female-predominant risk factors for CVD and examines the role of coronary artery calcium scores and certain biomarkers that can help further risk stratify patients and guide preventive recommendations.

Female-specific risk factors of parity and menopause age and risk of carotid plaque: the multi-ethnic study of atherosclerosis.

BACKGROUND: Female-specific factors of grand multiparity (≥5 births) and early menopause age are associated with an increased risk of cardiovascular disease (CVD). However, mechanisms are incompletely understood. Carotid plaque is a marker of subclinical atherosclerosis and associated with increased CVD risk. We evaluated the association of female-specific factors with plaque burden. METHODS: We included 2,313 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis, free of clinical CVD, whose parity and menopause age were ascertained by questionnaires and carotid plaque measured by ultrasound at baseline and 10 years later. Parity was categorized as nulliparity (reference), 1-2, 3-4 and ≥5 live births. Menopause age was categorized as <45, 45-49, 50-54 (reference) and ≥55 years. Multivariable regression was performed to evaluate the association of parity and menopause age with carotid plaque presence (yes/no) and extent [carotid plaque score (CPS)]. RESULTS: The mean age was 64±9 years; 52.3% had prevalent carotid plaque at baseline. Compared to nulliparity, grand multiparity was significantly associated with prevalent carotid plaque after adjustment for CVD risk factors (prevalence ratio 1.17 (95% CI 1.03-1.35)) and progression of CPS over 10 years [percent difference 13% (95% CI 3-23)]. There was not any significant association of menopause age with carotid plaque presence or progression in fully-adjusted models. CONCLUSION: In a multiethnic cohort, grand multiparity was independently associated with carotid plaque presence and progression. Early menopause, a known risk factor for CVD, was not captured by carotid plaque in this study. These findings may have implications for refining CVD risk assessment in women.

Re-Dosing del Nido cardioplegia in adult cardiac surgery: Perfusion characteristics and outcomes--Is there an optimal redosing strategy?

OBJECTIVES: del Nido cardioplegia is utilized for myocardial protection in adult patients undergoing cardiac surgery; however, no standardized re-dosing protocol exists. We describe perfusion characteristics and clinical outcomes in adult cardiac surgery patients who were re-dosed with del Nido cardioplegia. METHODS: Chart review was performed for adult patients undergoing cardiac surgery (specific inclusion/exclusion criteria below) who received exactly two doses of del Nido cardioplegia from 2012 to 2019; n = 542 patients. The main outcome was a composite endpoint comprised of operative mortality, myocardial infarction, post-operative cardiac support device (CSD), and postoperative decrease in ejection fraction (EF), which was analyzed via multivariable logistic regression (MVLR). A secondary analysis evaluated postoperative vasoactive-inotropic scores (VIS) via gamma log link regression (GLLR) as a more physiologic indication of myocardial recovery. RESULTS: MVLR demonstrated that increased total cardiopulmonary bypass (CPB) time was associated with a positive composite outcome (p < .001), whereas time between doses (p = .237) and the volume of each dose was not (p = .626). GLLR also demonstrated that prolonged CBP, decreased EF, congestive heart failure at time of surgery, and low hematocrit at the start of the surgery were all associated with higher VIS. CONCLUSIONS: In this retrospective study, variations in re-dosing strategy for del Nido cardioplegia do not affect postoperative outcomes and increased CPB time is associated with increased operative mortality, myocardial infarction, need for post-operative CSDs, and reduced postoperative EF, and increased VIS, irrespective of the re-dosing strategy. Further studies are warranted to to identify additional patient and operative characteristics that predispose to complications.

A Woman's Heart: Improving Uptake and Awareness of Cardiovascular Screening for Middle-Aged Populations.

Mid-life, the years leading up to and following the menopause transition, in women is accompanied by a change in cardiometabolic risk factors, including increases in body weight, changes in body composition, a more insulin-resistant state, and a shift towards a more atherogenic dyslipidemia pattern. Cardiovascular disease (CVD) risk assessment should be performed continually throughout the lifespan, as risk is not stagnant and can change throughout the life course. However, mid-life is a particularly important time for a woman to be evaluated for CVD risk so that appropriate preventive strategies can be implemented. Along with assessing traditional risk factors, ascertainment of a reproductive history is an integral part of a comprehensive CVD risk assessment to recognize unique female-specific or female-predominant factors that modify a woman's risk. When there is uncertainty about CVD risk and the net benefit of preventive pharmacotherapy interventions (such as statins), measuring a coronary artery calcium score can help further refine risk and guide shared decision-making. Additionally, there should be heightened sensitivity around identifying signs and symptoms of ischemic heart disease in women, as these may present differently than in men. Ischemia from coronary microvascular disease and/or vasospasm may be present even without obstructive coronary artery disease and is associated with a heightened risk for major cardiovascular events and reduced quality of life. Therefore, correctly identifying CVD in women and implementing preventive and treatment therapies is paramount. Unfortunately, women are underrepresented in cardiovascular clinical trials, and more data are needed about how to best incorporate novel and emerging risk factors into CVD risk assessment. This review outlines an approach to CVD screening and risk assessment in women using several methods, focusing on the middle-aged population.

Association between parity and markers of inflammation: The multi-ethnic study of atherosclerosis.

Introduction: Multiparity has been associated with increased risk of cardiovascular disease (CVD). Inflammation may be a mechanism linking parity to CVD. We investigated the association between parity and later-life markers of inflammation. Methods: We studied 3,454 female MESA participants aged 45-84, free of CVD, who had data on parity and inflammatory markers. Parity was categorized as 0 (reference), 1-2, 3-4, or ≥5. Linear regression was used to evaluate the association between parity and natural log-transformed levels of fibrinogen, D-dimer, GlycA, high sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6). Results: Mean age was 62 ± 10 years. The proportion of women with nulliparity, 1-2, 3-4, and ≥5 live births were 18, 39, 29, and 14%, respectively. There was no association between parity and fibrinogen. Women with grand multiparity (≥5 live births) had 28, 10, and 18% higher levels of hsCRP, IL-6 and D-dimer, respectively, compared to nulliparous women, after adjustment for demographic factors. After additional adjustment for CVD risk factors, women with 1-2 and 3-4 live births had higher hsCRP and women with 1-2 live births had higher GlycA. Conclusion: In this diverse cohort of middle-to-older aged women, we found that higher parity was associated with some inflammatory markers; however, these associations were largely attenuated after adjustment for CVD risk factors. There was no clear dose-response relationship between parity and these inflammatory markers. Future studies are needed to evaluate how inflammation may influence the link between parity and CVD and whether healthy lifestyle/pharmacotherapies targeting inflammation can reduce CVD risk among multiparous women. Clinical trial registration: The MESA cohort design is registered at clinicaltrials.gov as follows: https://clinicaltrials.gov/ct2/show/NCT00005487.

Parity History and Later Life Sex Hormone Levels in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Multiparity is a risk factor for cardiovascular disease (CVD). A more androgenic sex hormone profile, with a higher testosterone (T)/estradiol (E2) ratio, is associated with worse CVD outcomes in women and might be one mechanism linking multiparity to increased CVD risk. We investigated the relationship between parity and sex hormones at mid-to-older age. METHODS: We performed a cross-sectional analysis of 2979 women with data on parity and endogenous sex hormone levels from the Multi-Ethnic Study of Atherosclerosis (MESA), a community-based cohort. Parity and gravidity (our exposures) were categorized as 0 (reference), 1-2, 3-4, or ≥ 5. Our outcome measures were T, E2, sex hormone binding globulin, dehydroepiandrosterone, and T/E2 ratio. Progressively adjusted linear regression was used to evaluate the association of parity/gravidity with sex hormones. RESULTS: In multivariable adjusted models, there were no significant associations of parity with E2, dehydroepiandrosterone, and sex hormone binding globulin. Compared with nulliparity, after adjustment for CVD risk factors, women with 1-2 and 3-4 live births had higher T, but this was not significant for grand multiparity (≥ 5 live births). However, grand multigravidity (≥ 5 pregnancies) was associated with 10% (95% confidence interval [CI], 1%-20%) higher T and 14% (95% CI, 1%-29%) higher T/E2, compared with null gravidity. Grand multiparity was associated with an 18% (95% CI, 4%-34%) higher T/E2 ratio compared with nulliparity, after adjustment for CVD risk factors. CONCLUSIONS: In this multiethnic cohort, women with grand multigravidity and grand multiparity had higher T/E2 levels, reflecting a more androgenic sex hormone profile. Longitudinal studies on sex hormones' influence on the relationship between multiparity and CVD are warranted.

The Fourth Trimester: a Time for Enhancing Transitions in Cardiovascular Care.

Purpose of Review: The "fourth trimester" concept, defined as the first 12 weeks after delivery (and beyond), is a critical window of time for clinicians to intervene to optimize women's cardiovascular health after pregnancy. A timely and comprehensive postpartum cardiovascular assessment should be performed in all women following delivery in order to (1) follow up medical conditions present prior to conception, (2) evaluate symptoms and signs of common postpartum complications, and (3) identify risk factors and prevent future adverse cardiovascular outcomes. In this review, we aim to discuss major maternal cardiovascular risk factors such as hypertensive disorders of pregnancy, gestational diabetes mellitus, postpartum weight retention, and postpartum depression, as well as lactation as a potential protective risk modifying factor. Additionally, we will review effectiveness of outpatient interventions to enhance transitions in cardiovascular care during the fourth trimester. Recent Findings: A seamless hand-off from obstetric to primary care, and potentially cardiology, is needed for early detection and management of hypertension, weight, glycemic control, stress and mood, and long-term cardiovascular risk. Additionally, the use of telemedicine, blood pressure self-monitoring, remote activity monitoring, and behavioral health coaches are potentially feasible modalities to augment clinic-based care for cardiovascular risk factors and weight management, but additional studies are needed to study their long-term effectiveness. Summary: Development of a comprehensive postpartum care plan with careful consideration of each patient's risk profile and access to resources is critical to improve maternal morbidity and mortality, reduce health disparities, and achieve long-term cardiovascular health for women. Supporting postpartum well-being of women during this transition period requires a multidisciplinary approach, especially primary care engagement, and planning should start before delivery.

Assessing sex-based differences in postsurgical clinical outcomes after use of del Nido cardioplegia.

OBJECTIVES: del Nido cardioplegia is used to pharmacologically arrest the heart during cardiac surgery and decrease reperfusion- and ischaemia-related myocardial injury. Studies have demonstrated the physiological differences between male and female hearts, potentially related to cardiac size or myocyte calcium handling; we aimed to assess for between-sex differences in clinical outcomes after receipt of del Nido cardioplegia. METHODS: Patients who underwent coronary artery bypass or coronary artery bypass graft/valve surgery at our institution using del Nido cardioplegia (January 2014 to December 2019) were included (n = 2118). Clinical data were collected retrospectively. After the creation of a propensity-matched cohort (n = 1252), multivariable logistic regression was used to analyse binary postoperative outcomes, and a Gamma model was used for a continuous postoperative outcome. Our primary end-point was a composite end-point comprised of 30-day mortality and/or need for a post-bypass mechanical support device. RESULTS: The final cohort included 459 females and 793 males (matched up to 1:2, all standardized mean differences <0.1). Multivariable logistic regression showed that biological sex was not associated with the composite primary end-point (odds ratio = 0.898, P = 0.779). A Gamma model indicated that there were no sex-related differences in vasoactive-inotropic scores reflecting vasopressor and inotrope usage at the time of patient operating room exit (exp[est] = 1.394, P = 0.189). CONCLUSIONS: Our findings showed no significant between-sex differences in clinical outcomes after receiving del Nido cardioplegia, suggesting adequate myocardial protection as currently administered. Further research is warranted to elicit if there are sex-based differences between cardioplegic solutions. IRB APPROVAL DATE (PROTOCOL NUMBER): 26 May 2021 (AAAR8359).

Shared burden: the association between cancer diagnosis, financial toxicity, and healthcare cost-related coping mechanisms by family members of non-elderly patients in the USA.

PURPOSE: There has been little research on the healthcare cost-related coping mechanisms of families of patients with cancer. Therefore, we assessed the association between a cancer diagnosis and the healthcare cost-related coping mechanisms of participant family members through their decision to forego or delay seeking medical care, one of the manifestations of financial toxicity. METHODS: Using data from the National Health Interview Survey (NHIS) between 2000 and 2018, sample weight-adjusted prevalence was calculated and multivariable logistic regressions defined adjusted odds ratios (aORs) for participant family members who needed but did not get medical care or who delayed seeking medical care due to cost in the past 12 months, adjusting for relevant sociodemographic covariates, including participant history of cancer (yes vs. no) and participant age (18-45 vs. 46-64 years old). The analysis of family members foregoing or delaying medical care was repeated using a cancer diagnosis * age interaction term. RESULTS: Participants with cancer were more likely than those without a history of cancer to report family members delaying (19.63% vs. 16.31%, P < 0.001) or foregoing (14.53% vs. 12.35%, P = 0.001) medical care. Participants with cancer in the 18 to 45 years old age range were more likely to report family members delaying (pinteraction = 0.028) or foregoing (pinteraction < 0.001) medical care. Other factors associated with cost-related coping mechanisms undertaken by the participants' family members included female sex, non-married status, poorer health status, lack of health insurance coverage, and lower household income. CONCLUSION: A cancer diagnosis may be associated with familial healthcare cost-related coping mechanisms, one of the manifestations of financial toxicity. This is seen through delayed/omitted medical care of family members of people with a history of cancer, an association that may be stronger among young adult cancer survivors. These findings underscore the need to further explore how financial toxicity associated with a cancer diagnosis can affect patients' family members and to design interventions to mitigate healthcare cost-related coping mechanisms.

Adalimumab-Induced Lupus Nephritis: Case Report and Review of the Literature.

Tumor necrosis factor-alpha inhibitors are known causative agents of systemic lupus erythemato- sus but have rarely been implicated in lupus nephritis. A patient with Crohn's disease on long-term adalimumab treatment presented with new-onset Raynaud's phenomenon and was found to have hematuria and proteinuria. Elevated antinuclear, anti-dsDNA, and MPO antibodies were found. A renal biopsy confirmed the diagnosis of lupus nephritis. Adalimumab was discontinued ensuing improvement in urine studies and resolution of dsDNA and MPO antibodies. Adalimumab can induce systemic lupus erythematosus and lupus nephritis.

Controversies in the Use of Omega-3 Fatty Acids to Prevent Atherosclerosis.

PURPOSE OF REVIEW: We discuss current controversies in the clinical use of omega-3 fatty acids (FA), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and examine discrepancies between recent trials. Furthermore, we discuss potential side effects reported in these studies and the role of mixed omega-3 FA dietary supplements and concerns about their use. RECENT FINDINGS: REDUCE-IT showed that addition of icosapent ethyl, a highly purified form of EPA, can reduce risk of cardiovascular events among statin-treated individuals with high triglycerides. Additional supportive evidence for EPA has come from other trials and meta-analyses of omega-3 FA therapy. In contrast, trials of mixed EPA/DHA products have consistently failed to improve cardiovascular outcomes. Discrepancies in results reported in RCTs could be explained by differences in omega-3 FA products, dosing, study populations, and study designs including the placebo control formulation. Evidence obtained from highly purified forms should not be extrapolated to other mixed formulations, including "over-the-counter" omega-3 supplements. Targeting TG-rich lipoproteins represents a new frontier for mitigating ASCVD risk. Clinical and basic research evidence suggests that the use of omega-3 FA, specifically EPA, appears to slow atherosclerosis by reducing triglyceride-rich lipoproteins and/or inflammation, therefore addressing residual risk of clinical ASCVD.

New-onset lupus nephritis associated with COVID-19 infection.

A dysregulated immune response plays a critical role in systemic lupus erythematosus (SLE) pathogenesis. Environmental factors such as viruses, including coronavirus 2 (COVID-19), have been described to play a role in SLE presentation and exacerbation. These viruses trigger a host's humoral and cellular immunities typically essential in elimination of the viral infection. We present a case of a Hispanic male who developed new-onset lupus nephritis class II after a COVID-19 infection.

Multiparametric Approach for the Assessment of Mechanical Prosthetic Tricuspid Leaflet Function.

BACKGROUND: There is a lack of comprehensive echocardiographic data to allow discrimination of normal versus abnormal mechanical prosthetic tricuspid valve (MPTV) leaflet function. The identification of such parameters is essential to optimize diagnostic and therapeutic measures. METHODS: The authors investigated bileaflet MPTV function by comparing transthoracic echocardiographic data from 21 episodes of leaflet dysfunction due to valve thrombosis in 12 patients with data from 56 individuals with normal MPTV function. All episodes of dysfunction were confirmed by transesophageal echocardiography and/or cine fluoroscopy. Transthoracic echocardiography-derived two-dimensional, color, and spectral Doppler variables, including MPTV peak early diastolic velocity (E velocity), mean gradient, pressure half-time, time-velocity integral (TVI) of the MPTV, ratio of TVIMPTV to TVI of the left ventricular outflow tract (LVOT) and TVI of the right ventricular outflow tract (RVOT), and continuity-derived effective orifice area, were measured in both groups. RESULTS: Most episodes of MPTV dysfunction resulted from simultaneous involvement of both leaflets (57%), with leaflet(s) often immobilized in the open or semiopen position (71%). Transthoracic and transesophageal echocardiography performed similarly in detecting abnormal leaflet motion (90% vs 88%, P = .68), whereas transesophageal echocardiography was better in identifying MPTV thrombosis (31% vs 14%, respectively, P = .01). Color Doppler demonstrated flow propagation abnormalities in 67% of episodes of leaflet dysfunction but not in the control group (P < .0001). Doppler variables associated with MPTV leaflet dysfunction included E velocity > 1.6 m/sec, mean gradient > 5 mm Hg, PHT > 157 msec, TVIMPTV > 42 cm, TVIMPTV/TVILVOT > 2.3, TVIMPTV/TVIRVOT > 3.0, and continuity-derived effective orifice area ≤ 1.1 cm2, with most variables showing high and similar accuracy (area under the curve ≥ 95%). CONCLUSIONS: This study represents the first comprehensive echocardiographic assessment of MPTV leaflet dysfunction that provides parameters and criteria to distinguish normal versus abnormal prosthetic valve function.

Associations between endogenous sex hormone levels and adipokine levels in the Multi-Ethnic Study of Atherosclerosis.

Background: Differences in sex hormone levels contribute to differences in cardiovascular disease (CVD) risk. Adipokines play a role in cardiometabolic pathways and have differing associations with CVD. Adipokine levels differ by sex; however, the association between sex hormone profiles and adipokines is not well established. We hypothesized that a more androgenic sex hormone profile would be associated with higher leptin and resistin and lower adiponectin levels among postmenopausal women, with the opposite associations in men. Methods: We performed an analysis of 1,811 adults in the Multi-Ethnic Study of Atherosclerosis who had both sex hormones and adipokines measured an average of 2.6 years apart. Sex hormones [Testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), and dehydroepiandrosterone (DHEA)] were measured at exam 1; free T was estimated. Serum adipokines (leptin, resistin, adiponectin) were measured at exams 2 or 3. We used multivariable linear regression to examine the cross-sectional associations between sex hormones and adipokines. Results: The mean (SD) age was 63 (10) years, 48% were women; 59% non-White participants. For leptin, after adjusting for demographics only, higher free T and lower SHBG, were associated with higher leptin in women; this association was attenuated after further covariate adjustment. However in men, higher free T and lower SHBG were associated with greater leptin levels in fully adjusted models. For adiponectin, lower free T and higher SHBG were associated with greater adiponectin in both women and men after adjustment for CVD risk factors. For resistin, no significant association was found women, but an inverse association with total T and bioT was seen in men. Conclusion: Overall, these results further suggest a more androgenic sex profile (higher free T and lower SHBG) is associated with a less favorable adipokine pattern. These findings may provide mechanistic insight into the interplay between sex hormones, adipokines, and CVD risk.

Constrictive pericarditis following heart transplantation: Reality or fiction?

Constrictive pericarditis (CP) is a curable cause of diastolic heart failure with prior cardiac surgery being a recognizable etiology. We report a patient who developed CP one year following heart transplantation. Several clinical and imaging related factors may lead to diagnostic delays in similar patients, including the mistaken belief that transplanted hearts are devoid of pericardium and thus do not develop constriction. Post-transplantation pericardial effusion, mediastinitis, and cardiac rejection predispose to future CP. Caretakers should consider this entity in allograft recipients who develop heart failure symptoms of unclear etiology.

Ultrasound Imaging of the Abdominal Aorta: A Comprehensive Review.

Ultrasound is the imaging modality of choice for the initial evaluation of disorders that involve the abdominal aorta (AA). The diagnostic value of ultrasound resides in its ability to allow assessment of the anatomy and structure of the AA using two- dimensional, three-dimensional, and contrast-enhanced imaging. Moreover, ultrasound permits evaluation of the physiologic and hemodynamic consequences of abnormalities through Doppler interrogation of blood flow, thus enabling the identification and quantification of disorders within the AA and beyond its boundaries. The approach to ultrasound imaging of the AA varies, depending on the purpose of the study and whether it is performed in a radiology or vascular laboratory or in an echocardiography laboratory. The aim of this review is to demonstrate the usefulness of ultrasound imaging for the detection and evaluation of disorders that involve the AA, detail the abnormalities that are detected or further assessed, and outline its value for echocardiographers, sonographers, and radiologists.

Sex-Specific Plaque Signature: Uniqueness of Atherosclerosis in Women.

PURPOSE OF REVIEW: Cardiovascular disease is a leading cause of morbidity and mortality in both men and women, although there are notable differences in presentation between men and women. Atherosclerosis remains the predominant driver of coronary heart disease in both sexes; however, sex differences in atherosclerosis should be investigated further to understand clinical manifestations between men and women. RECENT FINDINGS: There are sex differences in the prevalence, progression, and prognostic impact of atherosclerosis. Furthermore, developing evidence demonstrates unique differences in atherosclerotic plaque characteristics between men and women on both noninvasive and invasive imaging modalities. Coronary microvascular dysfunction may be present even if no obstructive lesions are found. Most importantly, non-obstructive coronary artery disease is associated with a heightened risk of future adverse cardiovascular events and should not be ignored. The distinct plaque signature in women should be recognized, and optimal preventive strategies should be performed for both sexes.