Genetic Associations of Circulating Cardiovascular Proteins With Gestational Hypertension and Preeclampsia.

Importance: Hypertensive disorders of pregnancy (HDPs), including gestational hypertension and preeclampsia, are important contributors to maternal morbidity and mortality worldwide. In addition, women with HDPs face an elevated long-term risk of cardiovascular disease. Objective: To identify proteins in the circulation associated with HDPs. Design, Setting, and Participants: Two-sample mendelian randomization (MR) tested the associations of genetic instruments for cardiovascular disease-related proteins with gestational hypertension and preeclampsia. In downstream analyses, a systematic review of observational data was conducted to evaluate the identified proteins' dynamics across gestation in hypertensive vs normotensive pregnancies, and phenome-wide MR analyses were performed to identify potential non-HDP-related effects associated with the prioritized proteins. Genetic association data for cardiovascular disease-related proteins were obtained from the Systematic and Combined Analysis of Olink Proteins (SCALLOP) consortium. Genetic association data for the HDPs were obtained from recent European-ancestry genome-wide association study meta-analyses for gestational hypertension and preeclampsia. Study data were analyzed October 2022 to October 2023. Exposures: Genetic instruments for 90 candidate proteins implicated in cardiovascular diseases, constructed using cis-protein quantitative trait loci (cis-pQTLs). Main Outcomes and Measures: Gestational hypertension and preeclampsia. Results: Genetic association data for cardiovascular disease-related proteins were obtained from 21 758 participants from the SCALLOP consortium. Genetic association data for the HDPs were obtained from 393 238 female individuals (8636 cases and 384 602 controls) for gestational hypertension and 606 903 female individuals (16 032 cases and 590 871 controls) for preeclampsia. Seventy-five of 90 proteins (83.3%) had at least 1 valid cis-pQTL. Of those, 10 proteins (13.3%) were significantly associated with HDPs. Four were robust to sensitivity analyses for gestational hypertension (cluster of differentiation 40, eosinophil cationic protein [ECP], galectin 3, N-terminal pro-brain natriuretic peptide [NT-proBNP]), and 2 were robust for preeclampsia (cystatin B, heat shock protein 27 [HSP27]). Consistent with the MR findings, observational data revealed that lower NT-proBNP (0.76- to 0.88-fold difference vs no HDPs) and higher HSP27 (2.40-fold difference vs no HDPs) levels during the first trimester of pregnancy were associated with increased risk of HDPs, as were higher levels of ECP (1.60-fold difference vs no HDPs). Phenome-wide MR analyses identified 37 unique non-HDP-related protein-disease associations, suggesting potential on-target effects associated with interventions lowering HDP risk through the identified proteins. Conclusions and Relevance: Study findings suggest genetic associations of 4 cardiovascular disease-related proteins with gestational hypertension and 2 associated with preeclampsia. Future studies are required to test the efficacy of targeting the corresponding pathways to reduce HDP risk.

Cardiovascular Fellowship Training in Cardio-Obstetrics: JACC Review Topic of the Week.

The United States has the highest maternal mortality in the developed world with cardiovascular disease as the leading cause of pregnancy-related deaths. In response to this, the emerging subspecialty of cardio-obstetrics has been growing over the past decade. Cardiologists with training and expertise in caring for patients with cardiovascular disease in pregnancy are essential to provide effective, comprehensive, multidisciplinary, and high-quality care for this vulnerable population. This document provides a blueprint on incorporation of cardio-obstetrics training into cardiovascular disease fellowship programs to improve knowledge, skill, and expertise among cardiologists caring for these patients, with the goal of improving maternal and fetal outcomes.

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.

Clinical characteristics and subsequent need for anti-hypertensive agents in the postpartum period for hypertensive disorders of pregnancy.

OBJECTIVE: The objective of this study was to identify clinical characteristics of patients with hypertensive disorders of pregnancy associated with requiring multiple anti-hypertensive medications to optimize blood pressure in the postpartum setting. STUDY DESIGN: We performed a retrospective cohort study of all women who had a diagnosis of hypertensive disorders of pregnancy who delivered at a single institution between October 1, 2017 and May 1, 2021. Demographics and clinical characteristics including category of anti-hypertensive medication and number of medications were collected. Models were adjusted for race. RESULTS: A total of 1,708 women were identified for inclusion. Of this cohort, 64.9 % did not require any anti-hypertensive medications, while 24.8 % used one medication and 10.2 % required two or more medications. When comparing women by the number of medications that were required, their demographics were similar except for race (p < 0.001). Women taking two or more medications were most prescribed a beta blocker (94.9 %) followed by a calcium channel blocker (88.6 %). Women with a history of chronic hypertension had the highest risk of requiring two or more medications for blood pressure control (adjusted RR 11.19, 95 % CI 2.63-47.60). Chronic kidney disease also significantly increased the risk of requiring two or more medications (adjusted RR 3.09, 95 % CI 1.24-7.69). CONCLUSION: Women with chronic hypertension and chronic kidney disease are at increased risk for requiring multiple anti-hypertensive medications in the postpartum setting. We recommend frequent postpartum visits, either in person or implementing telemedicine platforms to optimize blood pressure control for this high-risk cohort.

Cardiovascular Complications During Delivery Admissions Associated With Assisted Reproductive Technology (from a National Inpatient Sample Analysis 2008 to 2019).

Women who conceive through assisted reproductive technology (ART) have a known increased risk of obstetric complications. However, whether ART is also associated with higher risk of developing cardiovascular complications during delivery admissions has not been well established. We used data from the National Inpatient Sample (2008 to 2019) and used the International Classification of Diseases codes to identify delivery hospitalizations and ART procedures. A total of 45,867,086 weighted delivery cases were identified, of which 0.24% were among women who conceived through ART (n = 108,542). Women with an ART history were older at the time of delivery (median 35 vs 28 years, p <0.01) and had a higher prevalence of hypertension, gestational diabetes, and dyslipidemia (all, p <0.01). After adjustment for age, race/ethnicity, co-morbidities, multiple gestation, insurance, and income, ART remained an independent predictor of peripartum cardiovascular complications, including pre-eclampsia/eclampsia (adjusted odds ratio [aOR] 1.48, 95% confidence interval [CI] 1.45 to 1.51), heart failure (aOR 1.94, 95% CI 1.10 to 3.40), and cardiac arrhythmias (aOR 1.39, 95% CI 1.30 to 1.48), compared with natural conception. Likewise, the risk of acute kidney injury (aOR 2.57, 95% CI 2.25 to 2.92), ischemic stroke (aOR 1.73, 95% CI 1.24 to 2.43), hemorrhagic stroke (aOR 1.63, 95% CI 1.27 to 2.11), pulmonary edema (aOR 2.29, 95% CI 2.02 to 2.61), and venous thromboembolism (aOR 1.92, 95% CI 1.63 to 2.25) were higher with ART. However, odds of developing peripartum cardiomyopathy or acute coronary syndrome were not associated with ART. Length of stay (3 vs 2 days, p <0.01) and cost of hospitalization ($5,903 vs $3,922, p <0.01) were higher for deliveries among women with a history of ART. In conclusion, women who conceived with ART had higher risk of pre-eclampsia, heart failure, arrhythmias, stroke, and other complications during their delivery hospitalizations. This may, in part, contribute to their increased resource utilization seen.

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.

Multimodality Imaging in the Detection of Ischemic Heart Disease in Women.

Women with coronary artery disease tend to have a worse short and long-term prognosis relative to men and the incidence of atherosclerotic cardiovascular disease is increasing. Women are less likely to present with classic anginal symptoms when compared with men and more likely to be misdiagnosed. Several non-invasive imaging modalities are available for diagnosing ischemic heart disease in women and many of these modalities can also assist with prognostication and help to guide management. Selection of the optimal imaging modality to evaluate women with possible ischemic heart disease is a scenario which clinicians often encounter. Earlier modalities such as exercise treadmill testing demonstrate significant performance variation in men and women, while newer modalities such as coronary CT angiography, myocardial perfusion imaging and cardiac magnetic resonance imaging are highly specific and sensitive for the detection of ischemia and coronary artery disease with greater parity between sexes. Individual factors, availability, diagnostic performance, and female-specific considerations such as pregnancy status may influence the decision to select one modality over another. Emerging techniques such as strain rate imaging, CT-myocardial perfusion imaging and cardiac magnetic resonance imaging present additional options for diagnosing ischemia and coronary microvascular dysfunction.

Cardio-Obstetrics: the Next Frontier in Cardiovascular Disease Prevention.

PURPOSE OF REVIEW: Internationally, cardiovascular disease (CVD) is the leading cause of death in women. With risk factors for CVD continuing to rise, early identification and management of chronic diseases such as hypertension, diabetes, and obstructive sleep apnea is necessary for prevention. Pregnancy is a natural stress test for women with risk factors who may be predisposed to CVD and offers a unique opportunity to not only recognize disease but also implement effective and long-lasting strategies for prevention. RECENT FINDINGS: Prevention begins before pregnancy, as preconception screening, counseling, and optimization of chronic diseases can improve maternal and fetal outcomes. Throughout pregnancy, women should maintain close follow-up, continued reevaluation of risk factors, with counseling when necessary. Continued healthcare engagement during the "fourth trimester," 3 months following delivery, allows clinicians to continue monitoring the evolution of chronic diseases, encourage ongoing lifestyle counseling, and connect women with primary care and appropriate specialists if needed. Unfortunately, this postpartum period represents a major care gap, as a significant proportion of most women do not attend their scheduled visits. Social determinants of health including decreased access to care and economic instability lead to increased risk factors throughout pregnancy but particularly play a role in poor compliance with postpartum follow-up. The use of telemedicine clinics and remote monitoring may prove to be effective interventions, bridging the gap between physicians and patients and improving follow-up for at-risk women. While many clinicians are beginning to understand the impact of CVD on women, screening and prevention strategies are not often implemented until much later in life. Pregnancy creates an opportunity to begin engaging women in cardiovascular protective strategies before the development of the disease.

Need for Better and Broader Training in Cardio-Obstetrics: A National Survey of Cardiologists, Cardiovascular Team Members, and Cardiology Fellows in Training.

Background Team-based models of cardio-obstetrics care have been developed to address the increasing rate of maternal mortality from cardiovascular diseases. Cardiovascular clinician and trainee knowledge and comfort with this topic, and the extent of implementation of an interdisciplinary approach to cardio-obstetrics, are unknown. Methods and Results We aimed to assess the current state of cardio-obstetrics knowledge, practices, and services provided by US cardiovascular clinicians and trainees. A survey developed in conjunction with the American College of Cardiology was circulated to a representative sample of cardiologists (N=311), cardiovascular team members (N=51), and fellows in training (N=139) from June 18, 2020, to July 29, 2020. Knowledge and attitudes about the provision of cardiovascular care to pregnant patients and the prevalence and composition of cardio-obstetrics teams were assessed. The widest knowledge gaps on the care of pregnant compared with nonpregnant patients were reported for medication safety (42%), acute coronary syndromes (39%), aortopathies (40%), and valvular heart disease (30%). Most respondents (76%) lack access to a dedicated cardio-obstetrics team, and only 29% of practicing cardiologists received cardio-obstetrics didactics during training. One third of fellows in training reported seeing pregnant women 0 to 1 time per year, and 12% of fellows in training report formal training in cardio-obstetrics. Conclusions Formalized training in cardio-obstetrics is uncommon, and limited access to multidisciplinary cardio-obstetrics teams and large knowledge gaps exist among cardiovascular clinicians. Augmentation of cardio-obstetrics education across career stages is needed to reduce these deficits. These survey results are an initial step toward developing a standard expectation for clinicians' training in cardio-obstetrics.

Developing a curriculum to improve cardiology fellows' training in pregnancy and cardiovascular disease.

BACKGROUND: Exposure to pregnant women with cardiovascular disease (CVD) during cardiology fellowship training is limited and without a standard curriculum in the United States. The authors sought to evaluate a dedicated curriculum to teach management of CVD in pregnancy to improve general cardiology fellowship training. METHODS: The authors developed a dedicated CVD in pregnancy curriculum for the general cardiology fellows at a large academic medical center in the fall of 2019. Fellows' knowledge was assessed via a board-style examination and exposure and attitudes related to the care of pregnant women with CVD were evaluated with a needs assessment questionnaire before and after the curriculum. RESULTS: Of the 17 fellows who participated in the curriculum, 12 completed the needs assessment pre-curriculum and 9 post-curriculum. The mean (SD) number of pregnant women with CVD cared for by each fellow in the inpatient and outpatient settings were 0.75 (1.29) and 0.56 (0.73), respectively. After the curriculum, all fellows reported awareness of available resources to treat pregnant women with CVD, while a majority disagreed that they receive regular exposure to pregnant patients with CVD in their training. The authors observed significant increases in fellows' confidence in their knowledge of normal cardiovascular physiology of pregnancy, physical exam skills, and ability to care for pregnant women with valvular disease and arrhythmias from pre to post-curriculum. A total of 15 fellows completed the board-style exam pre-curriculum and 15 post-curriculum. Fellows' performance on the board-style examination improved slightly from before to after the curriculum (64.0 to 75.3% correct, p = 0.02). CONCLUSIONS: A dedicated curriculum improved cardiology fellows' knowledge to recognize and treat CVD in pregnancy and improved confidence in caring for this unique patient population.

Cardiac and Obstetric Outcomes Associated With Mitral Valve Prolapse.

Mitral valve prolapse (MVP) is the most common valvular heart disease in women of reproductive age. Whether MVP increases the likelihood of adverse outcomes in pregnancy is unknown. The study objective was to examine the cardiac and obstetric outcomes associated with MVP in pregnant women. This retrospective cohort study, using the Healthcare Cost and Utilization Project National Readmission Sample database between 2010 and 2017, identified all pregnant women with MVP using the International Classification of Disease, Ninth and Tenth Revisions codes. The maternal cardiac and obstetric outcomes in pregnant women diagnosed with MVP were compared with women without MVP using multivariable logistic and Cox proportional hazard regression models adjusted for baseline demographic characteristics. There were 23,000 pregnancy admissions with MVP with an overall incidence of 16.9 cases per 10,000 pregnancy admissions. Pregnant women with MVP were more likely to die during pregnancy (adjusted hazard ratio 5.13, 95% confidence interval [CI] 1.09 to 24.16), develop cardiac arrest (adjusted odds ratio [aOR] 4.44, 95% CI 1.04 to 18.89), arrhythmia (aOR 10.96, 95% CI 9.17 to 13.12), stroke (aOR 6.90, 95% CI 1.26 to 37.58), heart failure (aOR 5.81, 95% CI 3.84 to 8.79), or suffer a coronary artery dissection (aOR 25.22, 95% CI 3.42 to 186.07) compared with women without MVP. Pregnancies with MVP were also associated with increased risks of preterm delivery (aOR 1.21, 95% CI 1.02 to 1.44) and preeclampsia/hemolysis, elevated liver enzymes, and low platelets syndrome (aOR 1.22, 95% CI 1.05 to 1.41). In conclusion, MVP in pregnancy is associated with adverse maternal cardiac outcomes and higher obstetric risks.

Prevalence of Left Ventricular Hypertrophy Caused by Systemic Hypertension Preceding the Development of Severe Aortic Stenosis.

It is generally assumed that left ventricular (LV) hypertrophy in aortic stenosis (AS) is a compensatory adaptation to chronic outflow obstruction. The advent of transcutaneous aortic valve replacement has stimulated more focus on AS in older patients, most of whom have antecedent hypertension. Accordingly, our aim was to investigate the interaction between hypertension and AS on LV remodeling in contemporary practice. We studied consecutive patients referred for echocardiograms with initial aortic valve (AV) peak velocity <3.0 m/s and a peak velocity of >3.5 m/s on a subsequent study performed at least 5 years later. LV size and geometry were measured echocardiographically. Midwall fractional shortening (FSmw) and peak systolic stress were calculated from 2-dimensional echocardiographic and Doppler data. Of 80 patients with progressive AS, 59% were women with mean age 82 ± 9 years. The average interval between the 2 echocardiograms was 5.9 ± 1.8 years. During the study period, peak velocity increased from 2.5 ± 0.4 to 4.2 ± 0.6 m/s (p < 0.01) and LV mass indexed to body surface area increased from 80 ± 28 to 122 ± 51 g/m2 (p < 0.01) with a corresponding shift from normal or concentric LV remodeling geometry to concentric hypertrophy. There was no correlation between change in LV mass index and AV mean gradient or valvulo-arterial impedance. However, change in LV mass index did correlate positively with initial peak velocity and inversely with initial LV mass. Plots of FSmw against circumferential stress at baseline and follow-up suggest that systolic function more than compensates for increasing load in many patients. In conclusion, most patients seen in our practice with severe AS have antecedent hypertension and LV remodeling at a time when outflow obstruction is mild. LV remodeling worsens in parallel with worsening severity of AS. Remodeling in these patients features increasing concentric remodeling of the LV, rather than LV dilation. Systolic function, as assessed by FSmw, remains compensated, or even improves relative to afterload, during progression of AS. Given these findings, we speculate that regression of LV hypertrophy to normal will not be affected by transcutaneous aortic valve replacement because LV hypertrophy preceded hemodynamically severe AS.

Dietary Habits and Medications to Control Hypertension Among Women of Child-Bearing Age in the United States from 2001 to 2016.

BACKGROUND: Hypertension (HTN) in pregnancy is a leading cause of maternal morbidity and mortality in the United States. Although the Dietary Approaches to Stop Hypertension (DASH) diet is recommended for all adults with HTN, rates of DASH adherence and antihypertensive medication use in women of child-bearing age are unknown. Our objectives were to determine DASH adherence and antihypertensive medication use in women of child-bearing age. METHODS: In the National Health and Nutrition Examination Surveys from 2001 to 2016, we estimated DASH adherence among women of child-bearing age (20-50 years). We derived a DASH score (0-9) based on 9 nutrients, with DASH adherence defined as DASH score ≥4.5. HTN was defined by blood pressure (BP) ≥130/80 mm Hg or antihypertensive medication use. DASH scores were compared across BP categories and antihypertensive medication use was categorized. RESULTS: Of the 7,782 women, the mean age (SE) was 32.8 (0.2) years, 21.4% were non-Hispanic Black, and 20.3% had HTN. The mean DASH score was 2.11 (0.06) for women with self-reported HTN and 2.40 (0.03) for women with normal BP (P < 0.001). DASH adherence was prevalent in 6.5% of women with self-reported HTN compared with 10.1% of women with normal BP (P < 0.05). Self-reported HTN is predominantly managed with medications (84.8%), while DASH adherence has not improved in these women from 2001 to 2016. Moreover, 39.5% of US women of child-bearing age are taking medications contraindicated in pregnancy. CONCLUSIONS: Given the benefits of optimized BP during pregnancy, this study highlights the critical need to improve DASH adherence and guide prescribing among women of child-bearing age.

Effect of Transaortic Valve Intervention for Aortic Stenosis on Myocardial Mechanics.

Chronic afterload excess in aortic stenosis results in compensatory concentric hypertrophy which mitigates the increased systolic load. Surgical aortic valve replacement has been shown to decrease afterload and improve left ventricular (LV) ejection fraction (EF). The extent to which these changes take place in patients undergoing TAVI (transcatheter aortic valve intervention) may be different than what has been observed in the surgical aortic valve replacement patients who were generally younger with few co-morbidities. Accordingly, we analyzed indices of LV structure and ventricular mechanics pre- and 1-year after TAVI in 397 patients (mean age 81±9, 46% women) with severe symptomatic aortic stenosis, complete echocardiographic data was available in 156 patients and these patients compromised our study population. Our principal findings are: (1) LV remodeling occurs after TAVI; (2) afterload decreases significantly; (3) LV chamber and myocardial function, assessed by left ventricular ejection fraction and midwall fractional shortening, and stroke volume, respectively, remain unchanged or decrease. In conclusion, TAVI effects LV remodeling despite significant co-morbidities. Thus, TAVI reduces afterload and leads to LV remodeling. Surprisingly, however, systolic function does not improve. These data run counter to the paradigm that afterload reduction improves systolic function and suggest that the response to afterload reduction is complex in the TAVI population.

Recurrent and Life-Threatening Peripartum Cardiomyopathy: Diagnosis, Delivery Considerations, and Management.

Peripartum cardiomyopathy is an idiopathic reduction in left ventricular systolic function (ejection fraction <45%) toward the end of pregnancy or in the months after delivery. A multidisciplinary approach to management with shock team support is key to identifying and adequately treating patients with refractory heart failure and peripartum cardiomyopathy. (Level of Difficulty: Intermediate.).