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.

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..

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.

Sex Differences in Faculty Rank Among Academic Cardiologists in the United States.

BACKGROUND: Studies demonstrate that women physicians are less likely than men to be full professors. Comprehensive evidence examining whether sex differences in faculty rank exist in academic cardiology, adjusting for experience and research productivity, is lacking. Therefore, we evaluated for sex differences in faculty rank among a comprehensive, contemporary cohort of US cardiologists after adjustment for several factors that impact academic advancement, including measures of clinical experience and research productivity. METHODS: We identified all US cardiologists with medical school faculty appointments in 2014 by using the American Association of Medical Colleges faculty roster and linked this list to a comprehensive physician database from Doximity, a professional networking website for doctors. Data on physician age, sex, years since residency, cardiology subspecialty, publications, National Institutes of Health grants, and registered clinical trials were available for all academic cardiologists. We estimated sex differences in full professorship, adjusting for these factors and medical school-specific fixed effects in a multivariable regression model. RESULTS: Among 3810 cardiologists with faculty appointments in 2014 (13.3% of all US cardiologists), 630 (16.5%) were women. Women faculty were younger than men (mean age, 48.3 years versus 53.5 years, P<0.001), had fewer total publications (mean number: 16.5 publications versus 25.2 publications; P<0.001), were similarly likely to have National Institutes of Health funding (proportion with at least 1 National Institutes of Health award, 10.8% versus 10.4%; P=0.77), and were less likely to have a registered clinical trial (percentage with at least 1 clinical trial, 8.9% versus 11.1%; P=0.10). Among 3180 men, 973 (30.6%) were full professors in comparison with 100 (15.9%) of 630 women. In adjusted analyses, women were less likely to be full professors than men (adjusted odds ratio, 0.63; 95% confidence interval, 0.43-0.94; P=0.02; adjusted proportions, 22.7% versus 26.7%; absolute difference, -4.0%; 95% confidence interval, -7.5% to -0.7%). CONCLUSIONS: Among cardiology faculty at US medical schools, women were less likely than men to be full professors after accounting for several factors known to influence faculty rank.

Aspirin Use in Women: Current Perspectives and Future Directions.

PURPOSE OF REVIEW: This review examines the recent literature on the use of low-dose aspirin (LDA) for primary and secondary prevention of cardiovascular disease in women, use of LDA for pre-eclampsia prevention in pregnancy, and the underutilization of aspirin therapy in women as compared to men. RECENT FINDINGS: While men and women should not differ with respect to aspirin use for secondary prevention, its role in primary prevention remains unclear for both sexes, with particular uncertainty in women. Reflective of this are conflicting recommendations in current guidelines for primary prevention and thus investigations of primary prevention aspirin use are ongoing and will play an important role in elucidating its efficacy. While there is significant heterogeneity in studies to date of LDA for pre-eclampsia prevention, based on recent meta-analyses suggesting promising results, guidelines now recommend initiation in high risk women after the 12th week of gestation. Finally, studies consistently reveal that aspirin therapy is underutilized in women as compared to men, suggesting a need to better educate physicians and the general public about its use in women. Further research is needed to better elucidate the role of aspirin in women for primary prevention of cardiovascular disease and for pre-eclampsia in high risk pregnant women. In addition, further investigation into the factors that lead to the current underutilization of aspirin in women are required in order to ensure that patients of both sexes are optimally treated, with the goal of improving cardiovascular outcomes in all patients.

Biomarkers in ACS and heart failure: should men and women be interpreted differently?

BACKGROUND: Sex-based differences exist in the circulating concentrations of certain novel and established biomarkers in patients with acute coronary syndromes (ACS) and heart failure (HF). However, to date, few studies have compared the diagnostic and prognostic utility of these markers in men vs women. CONTENT: This mini-review contains a discussion of the published reports of studies that have explored whether differences in biomarker concentrations exist between men and women with ACS or HF. It also examines those studies that have compared the utility of biomarkers for diagnosis or risk stratification in women vs men. Because biomarkers are often used to make therapeutic and triage decisions in patient care, the potential clinical implications for any observed differences in biomarker reference limits for men and women is discussed. SUMMARY: Although the concentration distributions may differ between men and women for certain biomarkers in clinical use, the clinical implications of these observations remain unclear. Because elements of the pathophysiology of ACS and HF may differ between the sexes, further research is needed to better evaluate the diagnostic and prognostic utility of biomarkers in men vs women.

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.

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.

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.

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.

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.

Developmental dynamics of piriform cortex.

The piriform cortex (PCX) is a trilaminar paleocortex that is of interest for its role in odor coding and as a model for studying general principles of cortical sensory processing. While the structure of the mature PCX has been well characterized, its development is poorly understood. Notably, the kinetics as well as the cellular and morphological basis of the postnatal events that shape the PCX remain unknown. We followed the cellular fates of early- versus late-born cells in layer II of the anterior PCX, with a focus on the molecular maturation of pyramidal cells and the kinetics of their differentiation. We showed that: 1) early-born pyramidal cells differentiate more rapidly than late-born cells and 2) the position of pyramidal cells within the thickness of layer II determines the kinetics of their molecular maturation. We then examined the postnatal development of cortical lamination and showed that the establishment of inhibitory networks in the PCX proceeds through an increase in the density of inhibitory synapses despite a decrease in the number of interneurons. Together, our results provide a more comprehensive view of the postnatal development of the anterior PCX and reveal both similarities and differences in the development of this paleocortex versus the neocortex.

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.

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.

The Utilization and Interpretation of Cardiac Biomarkers During Pregnancy: JACC: Advances Expert Panel.

Cardiac biomarkers are widely used in the nonpregnant population when acute cardiovascular (CV) pathology is suspected; however, the behavior of these biomarkers in the context of pregnancy is less well understood. Pregnant individuals often have symptoms that mimic those of cardiac dysfunction, and complications of pregnancy may include CV disease. This paper will summarize our current knowledge on the use of cardiac biomarkers in pregnancy and provide suggestions on how to use these tools in clinical practice based on the available evidence. Natriuretic peptides and troponin should not be measured routinely in uncomplicated pregnancy, where values should remain low as in the nonpregnant population. In the context of pre-existing or suspected CV disease, these biomarkers retain their negative predictive value. Elevations of both natriuretic peptides and troponin may occur without clear clinical significance in the immediate postpartum period. Elevations of these markers should always prompt further investigation into possible CV pathology.