Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator-activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Coronary Microvascular Function Following Severe Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (ß, -0.67 [95% CI, -1.21 to -0.13]; P=0.016), lower stress myocardial blood flow (ß, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P=0.001), and higher stress coronary vascular resistance (ß, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P=0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (r=0.71; P<0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.

Coronary Microvascular Function Following Severe Preeclampsia.

Background: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating pro- and anti-angiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. Methods: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography (PET) within 4 weeks of delivery. A control group of pre-menopausal, non-postpartum women was also included. Myocardial flow reserve (MFR), myocardial blood flow (MBF), and coronary vascular resistance (CVR) were compared across groups. Soluble fms-like tyrosine kinase receptor-1 (sFlt-1) and placental growth factor (PlGF) were measured at imaging. Results: The primary cohort included 19 women with severe preeclampsia (imaged at a mean 16.0 days postpartum), 5 with normotensive pregnancy (mean 14.4 days postpartum), and 13 non-postpartum female controls. Preeclampsia was associated with lower MFR (ß=-0.67 [95% CI -1.21 to -0.13]; P=0.016), lower stress MBF (ß=-0.68 [95% CI, -1.07 to -0.29] mL/min/g; P=0.001), and higher stress CVR (ß=+12.4 [95% CI 6.0 to 18.7] mmHg/mL/min/g; P=0.001) vs. non-postpartum controls. MFR and CVR after normotensive pregnancy were intermediate between preeclamptic and non-postpartum groups. Following preeclampsia, MFR was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest MBF (r=0.71; P<0.001), independent of hemodynamics. Conclusions: In this exploratory study, we observed reduced coronary microvascular function in the early postpartum period following severe preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves the coronary microcirculation. Further research is needed to establish interventions to mitigate risk of preeclampsia-associated cardiovascular disease.

Maternal Cardiovascular Health Post-Dobbs.

Maternal Cardiovascular Health Post-DobbsPregnancy is associated with increasing morbidity and mortality in the United States. In the post-Dobbs era, many pregnant patients at highest risk no longer have access to abortion, which has been a crucial component of standard medical care.

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.

Cardiogenic Shock and Utilization of Mechanical Circulatory Support in Pregnancy.

Maternal mortality rates are rising in the United States, a trend which is in contrast to that seen in other high-income nations. Cardiovascular disease and hypertensive disorders of pregnancy are consistently the leading causes of maternal mortality both in the United States and globally, accounting for about one-quarter to one-third of maternal and peripartum deaths. A large proportion of cardiovascular morbidity and mortality stems from acquired disease in the context of cardiovascular risk factors, which include obesity, pre-existing diabetes and hypertension, and inequities in care from maternal care deserts and structural racism. Patients may also become pregnant with preexisting structural heart disease, or acquire disease throughout pregnancy (ex: spontaneous coronary artery dissection, peripartum cardiomyopathy), and be at higher risk of pregnancy-related cardiovascular complications. While risk-stratification tools including the modified World Health Organization (mWHO) classification, Cardiac Disease in Pregnancy (CARPREG II) and Zwangerschap bij Aangeboren HARtAfwijking/Pregnancy in Women with Congenital Heart Disease (ZAHARA) have been designed to help physicians identify patients at increased risk for adverse pregnancy outcomes and who may therefore benefit from referral to a tertiary care center, the limitation of these scores is their predominant focus on patients with known preexisting heart disease. As such, identifying patients at risk for pregnancy complications presents a significant challenge, and it is often patients with high-risk cardiovascular substrates prior to or during pregnancy who are at a highest risk for adverse pregnancy outcomes including cardiogenic shock.

Multiple Prior Live Births Are Associated With Cardiac Remodeling and Heart Failure Risk in Women.

OBJECTIVE: Greater parity has been associated with cardiovascular disease risk. We sought to find whether the effects on cardiac remodeling and heart failure risk are clear. METHODS: We examined the association of number of live births with echocardiographic measures of cardiac structure and function in participants of the Framingham Heart Study (FHS) using multivariable linear regression. We next examined the association of parity with incident heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction using a Fine-Gray subdistribution hazards model in a pooled analysis of n = 12,635 participants in the FHS, the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular Endstage Disease. Secondary analyses included major cardiovascular disease, myocardia infarction and stroke. RESULTS: Among n = 3931 FHS participants (mean age 48 ± 13 years), higher numbers of live births were associated with worse left ventricular fractional shortening (multivariable ß -1.11 (0.31); P = 0.0005 in ≥ 5 live births vs nulliparous women) and worse cardiac mechanics, including global circumferential strain and longitudinal and radial dyssynchrony (P < 0.01 for all comparing ≥ 5 live births vs nulliparity). When examining HF subtypes, women with ≥ 5 live births were at higher risk of developing future HFrEF compared with nulliparous women (HR 1.93, 95% CI 1.19-3.12; P = 0.008); by contrast, a lower risk of HFpEF was observed (HR 0.58, 95% CI 0.37-0.91; P = 0.02). CONCLUSIONS: Greater numbers of live births are associated with worse cardiac structure and function. There was no association with overall HF, but a higher number of live births was associated with greater risk for incident HFrEF.

Radiation protection for healthcare professionals working in catheterisation laboratories during pregnancy: a statement of the European Association of Percutaneous Cardiovascular Interventions (EAPCI) in collaboration with the European Heart Rhythm Association (EHRA), the European Association of Cardiovascular Imaging (EACVI), the ESC Regulatory Affairs Committee and Women as One.

The European Association of Percutaneous Cardiovascular Interventions (EAPCI), the European Heart Rhythm Association (EHRA), the European Association of Cardiovascular Imaging (EACVI), the European Society of Cardiology (ESC) Regulatory Affairs Committee and Women as One support continuous review and improvement, not only in the practice of assuring patients a high quality of care but also in providing health professionals with support documents to help them in their career and enhance gender equity. Recent surveys have revealed that radiation exposure is commonly reported as the primary barrier for women pursuing a career in interventional cardiology or cardiac electrophysiology (EP). The fear of foetal exposure to radiation during pregnancy may lead to a prolonged interruption in their career. Accordingly, this joint statement aims to provide a clear statement on radiation risk and the existing data on the experience of radiation-exposed cardiologists who continue to work in catheterisation laboratories (cath labs) throughout their pregnancies. In order to reduce the barrier preventing women from accessing these careers, increased knowledge in the community is warranted. Finally, by going beyond simple observations and review of the literature, our document suggests proposals for improving workplace safety and for encouraging equity.

First Trimester Cardiac Biomarkers among Women with Peripartum Cardiomyopathy: Are There Early Clues to This Late-Pregnancy Phenomenon?

OBJECTIVE: Whether biomarkers may enable early identification of women who develop peripartum cardiomyopathy (PPCM) prior to disease onset remains a question of interest. STUDY DESIGN: A retrospective nested case-control study was conducted to determine whether first trimester N-terminal pro-B type natriuretic peptide (NT-proBNP) or high sensitivity cardiac troponin I (hs-cTnI) differed among women who developed PPCM versus unaffected pregnancies. Cases were matched to unaffected women by age, race, parity, and gestational age of sample (control A) and then further by blood pressure and pregnancy weight gain (control B). RESULTS: First trimester NT-proBNP concentrations were numerically higher among women who subsequently developed PPCM (116 pg/mL [83-177]) as compared with women in control A (56.1 pg/mL [38.7-118.7], p = 0.3) or control B (37.6 [23.3 - 53.8], p <0.05). A higher proportion of women who subsequently developed PPCM (50%) had detectable levels of hs-cTnI as compared with control A (0%, p = 0.03) or control B (18.8%, p = 0.52). Among both cases and controls, hs-cTnI values were low and often below the limit of detection. CONCLUSION: There were differences in first trimester NT-proBNP and hs-cTnI concentrations between women who subsequently developed PPCM and those who did not, raising the possibility the early pregnancy subclinical myocardial dysfunction may be associated with this late-pregnancy disease. KEY POINTS: · First trimester NT-proBNP is numerically higher among women who subsequently develop PPCM.. · First trimester hs-cTnI was nominally higher among women who developed PPCM versus those who did not.. · A significant proportion of normal pregnant women have undetectable hs-cTnI..

Childbearing Among Women Cardiologists: The Interface of Experience, Impact, and the Law.

BACKGROUND: Maternity leave is highly variable in the United States given the lack of a federal workforce mandate. OBJECTIVES: The purpose of this study was to describe the experiences and impact of childbearing on women cardiologists and their careers, within a legal framework. METHODS: A survey was sent to women cardiologists, asking about their experiences while pregnant and on maternity leave. The incidence of complications and career impacts on the cardiologists was assessed. RESULTS: Of 323 respondents who had been pregnant as a practicing cardiologist, extra service or call before maternity leave was required in 37.2%. Of those who performed extra service or call, 17.5% were placed on bedrest before delivery, compared with 7.4% who did not perform extra service or call (P = 0.005). During the year of pregnancy, 41.2% experienced a salary decrease; only 7.4% had their relative value units prorated for time on maternity leave; 23.2% had no paid maternity leave. Self-reported pregnancy complications occurred in 36.5%, those with complications had a 60% greater chance of reporting that pregnancy adversely affected their career, compared with those without complications. Nearly three-fourths (237 respondents) reported experiencing at least one of several troubling practices that are illegal in many circumstances. CONCLUSIONS: Women cardiologists report wide variances in maternity leave in the United States, with many experiencing likely violations of the Family and Medical Leave Act or other statues. Childbearing issues in cardiologists should be addressed to improve the professional and personal lives of women cardiologists and the attractiveness of cardiology to potential trainees.

Interventions to Mitigate Risk of Cardiovascular Disease After Adverse Pregnancy Outcomes: A Review.

IMPORTANCE: A growing body of evidence suggests that adverse pregnancy outcomes (APOs), including hypertensive disorders of pregnancy, gestational diabetes (GD), preterm birth, and intrauterine growth restriction, are associated with increased risk of cardiometabolic disease and cardiovascular disease (CVD) later in life. Adverse pregnancy outcomes may therefore represent an opportunity to intervene to prevent or delay onset of CVD. The objective of this review was to summarize the current evidence for targeted postpartum interventions and strategies to reduce CVD risk in women with a history of APOs. OBSERVATIONS: A search of PubMed and Ovid for English-language randomized clinical trials, cohort studies, descriptive studies, and guidelines published from January 1, 2000, to April 30, 2021, was performed. Four broad categories of interventions were identified: transitional clinics, lifestyle interventions, pharmacotherapy, and patient and clinician education. Observational studies suggest that postpartum transitional clinics identify women who are at elevated risk for CVD and may aid in the transition to longitudinal primary care. Lifestyle interventions to increase physical activity and improve diet quality may help reduce the incidence of type 2 diabetes in women with prior GD; less is known about women with other prior APOs. Metformin hydrochloride may prevent development of type 2 diabetes in women with prior GD. Evidence is lacking in regard to specific pharmacotherapies after other APOs. Cardiovascular guidelines endorse using a history of APOs to refine CVD risk assessment and guide statin prescription for primary prevention in women with intermediate calculated 10-year CVD risk. Research suggests a low level of awareness of the link between APOs and CVD among both patients and clinicians. CONCLUSIONS AND RELEVANCE: These findings suggest that transitional clinics, lifestyle intervention, targeted pharmacotherapy, and clinician and patient education represent promising strategies for improving postpartum maternal cardiometabolic health in women with APOs; further research is needed to develop and rigorously evaluate these interventions. Future efforts should focus on strategies to increase maternal postpartum follow-up, improve accessibility to interventions across diverse racial and cultural groups, expand awareness of sex-specific CVD risk factors, and define evidence-based precision prevention strategies for this high-risk population.

Increasing Participation of Women in Cardiovascular Trials: JACC Council Perspectives.

Although some progress has been made in the last 3 decades to increase the number of women in clinical cardiology trials, review of recent cardiovascular literature demonstrates that women and underrepresented minority women are still underrepresented in most clinical cardiology trials. This is especially notable in trials of patients with coronary artery disease, heart failure with reduced ejection fraction, and arrhythmia studies, especially those involving devices and procedures. Despite the call from National Institutes of Health, Food and Drug Administration, Institute of Medicine, and various professional societies, the gap remains. This paper seeks to identify the barriers for low enrollment and retention from patient, clinician, research team, study design, and system perspectives, and offers recommendations to improve recruitment and retention in the current era.

Echocardiography for the Pregnant Heart.

PURPOSE OF REVIEW: Pregnancy is associated with significant hemodynamic changes, making it a potentially high-risk period for women with underlying cardiovascular disease. Echocardiography remains the preferred modality for diagnosis and monitoring of pregnant women with cardiovascular disease as it is widely available and does not require radiation. This paper reviews the role of echocardiography along the continuum of pregnancy in at-risk patients, with a focus on key cardiac disease states in pregnancy. RECENT FINDINGS: In the preconception stage, risk stratification scores such as CARPREG II, ZAHARA and the modified WHO remain central to counseling and planning. As such, echocardiography serves an important role in assessing the severity of pre-existing structural disease. Among women with pre-existing cardiovascular disease who become pregnant-as well as those who develop cardiovascular symptoms during pregnancy-echocardiography is a key imaging tool for assessment of hemodynamic and structural changes and is recommended as the first-line imaging modality when appropriate by both the American College of Obstetricians and Gynecologists (ACOG) and the Food and Drug Administration (FDA). However, routine screening intervals during pregnancy for various cardiac lesions are not well defined, resulting in clinical heterogeneity in care. SUMMARY: Echocardiography is the imaging modality of choice for defining, risk stratifying, and monitoring cardiovascular changes throughout pregnancy. Once identified, at-risk patients should receive careful individual counseling and follow-up with a multidisciplinary team. Echocardiography serves as a widely available tool for serial monitoring of pregnant women with cardiovascular disease throughout pregnancy and the postpartum period.

Galectin-3 Inhibition With Modified Citrus Pectin in Hypertension.

We investigated the effect of galectin-3 (Gal-3) inhibition with modified citrus pectin on markers of collagen metabolism in a proof-of-concept randomized placebo-controlled trial of participants with elevated Gal-3 levels and hypertension. Although higher Gal-3 levels were associated with female sex, diabetes, and reduced glomerular filtration rate in cross-sectional analyses, treatment with modified citrus pectin did not change collagen markers. The effect of Gal-3 inhibition among individuals with heart failure warrants further investigation.

Establishing Better Evidence on Remote Monitoring for Postpartum Hypertension: A Silver Lining of the Coronavirus Pandemic.

The transformation of our health care system in response to coronavirus disease 2019 (COVID-19) provides a unique opportunity to examine the use of telehealth for postpartum care. The postpartum period can pose significant risks and challenges, particularly for women with hypertensive disorders of pregnancy. Remote blood pressure monitoring has proven feasible and acceptable among women and providers but has not been widely implemented or researched. Early studies have identified improved outcomes with use of telehealth, including increased compliance with care and decreased disparity in hypertension follow-up. Preliminary data make a compelling case for remote monitoring as a promising treatment strategy to manage postpartum hypertension. Remote monitoring technology should be incorporated as a standard component for the comprehensive management of postpartum hypertension during COVID-19. As a consequence of the pandemic, we now have an opportunity to research the impact of postpartum remote blood pressure monitoring on maternal outcome and disparities within these outcomes.

Menopausal age and left ventricular remodeling by cardiac magnetic resonance imaging among 14,550 women.

The present study included 14,550 postmenopausal female participants in the UK Biobank who completed cardiac magnetic resonance imaging. Earlier age at menopause was significantly and independently associated with smaller left ventricular end-diastolic volume and smaller stroke volume, a pattern suggesting acceleration of previously described age-related left ventricular remodeling. These findings may have implications for understanding mechanisms of heart failure, specifically heart failure with preserved ejection fraction, among women with early menopause.