Cardiovascular risk assessment in women: which women are suited for menopausal hormone therapy?

Individual risk assessment for atherosclerotic cardiovascular disease is important for safe menopausal hormone prescription. Besides the traditional risk factors, female-specific risk variables related to pregnancy and gynecologic conditions importantly contribute to a more tailored risk assessment in women at middle age. Of these, prior pre-eclampsia/HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome and early spontaneous menopause (<40 years) seem to be the strongest adverse risk variables. Concomitant inflammatory disorders should also be taken into account. Adding a coronary artery calcium score with a computed tomography scan to risk assessment has a high predictive value for future cardiovascular events. This should be considered to discriminate between low-risk and high-risk women when uncertainty exists. In women at intermediate risk, menopausal hormone therapy can be easily combined with preventive medication if cardiovascular risk factors are present. In women at higher risk who have severe disabling vasomotor symptoms, a lower dosage of hormone therapy can be considered in good collaboration between the gynecologist and the cardiologist/vascular specialist.

Design and rationale of the NetherLands registry of invasive Coronary vasomotor Function Testing (NL-CFT).

BACKGROUND: Angina without angiographic evidence of obstructive coronary artery disease (ANOCA) is a highly prevalent condition with insufficient pathophysiological knowledge and lack of evidence-based medical therapies. This affects ANOCA patients prognosis, their healthcare utilization and quality of life. In current guidelines, performing a coronary function test (CFT) is recommended to identify a specific vasomotor dysfunction endotype. The NetherLands registry of invasive Coronary vasomotor Function testing (NL-CFT) has been designed to collect data on ANOCA patients undergoing CFT in the Netherlands. METHODS: The NL-CFT is a web-based, prospective, observational registry including all consecutive ANOCA patients undergoing clinically indicated CFT in participating centers throughout the Netherlands. Data on medical history, procedural data and (patient reported) outcomes are gathered. The implementation of a common CFT protocol in all participating hospitals promotes an equal diagnostic strategy and ensures representation of the entire ANOCA population. A CFT is performed after ruling out obstructive coronary artery disease. It comprises of both acetylcholine vasoreactivity testing as well as bolus thermodilution assessment of microvascular function. Optionally, continuous thermodilution or Doppler flow measurements can be performed. Participating centers can perform research using own data, or pooled data will be made available upon specific request via a secure digital research environment, after approval of a steering committee. CONCLUSION: NL-CFT will be an important registry by enabling both observational and registry based (randomized) clinical trials in ANOCA patients undergoing CFT.

Cardiometabolic health in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is an increasing public health problem with a prevalence now approaching 4%. POI results in adverse effects on the skeleton and central nervous system as well as disturbances of metabolic and cardiological factors that predispose to a major increased risk of cardiovascular disease (CVD). This article reviews the effects of the premature loss of ovarian function on lipids and lipoproteins, glucose and insulin metabolism, body composition, hemostasis and blood pressure, together with effects on the development of metabolic syndrome and diabetes mellitus. The article examines the effects of POI on vascular endothelial function and inflammation that result in arterial disease, and reviews the effects of hormone replacement therapy (HRT) on these various metabolic processes and on cardiovascular outcomes. It is essential that women with POI receive hormonal treatment to help prevent the development of CVD, and that this treatment is continued at least until the normal age of menopause. It appears that HRT has a more favorable effect than the combined oral contraceptive, but larger clinical trials are needed to establish the optimal treatment. Other therapeutic measures may need to be added to correct existing metabolic abnormalities and, in particular, attention to lifestyle factors such as diet and exercise must be encouraged.

Diagnostic approach in patients with angina and no obstructive coronary artery disease: emphasising the role of the coronary function test.

BACKGROUND: Many patients with angina do not have obstructive coronary artery disease (CAD), also referred to as "Ischaemia with No Obstructive Coronary Arteries" (INOCA). Coronary vascular dysfunction is the underlying cause of this ischaemic heart disease in as much as 59-89% of these patients, including the endotypes of coronary microvascular dysfunction and epicardial coronary vasospasm. Currently, a coronary function test (CFT) is the only comprehensive diagnostic modality to evaluate all endotypes of coronary vascular dysfunction in patients with INOCA. OBJECTIVE: In this paper we discuss the relevance of performing a CFT, provide considerations for patient selection, and present an overview of the procedure and its safety. METHODS: We reviewed the latest published data, guidelines and consensus documents, combined with a discussion of novel original data, to present this point of view. RESULTS: The use of a CFT could lead to a more accurate and timely diagnosis of vascular dysfunction, identifies patients at risk for cardiovascular events, and enables stratified treatment which improves symptoms and quality of life. Current guidelines recommend considering a CFT in patients with INOCA and persistent symptoms. The safety of the procedure is comparable to that of a regular coronary angiography with physiological measurements. Non-invasive alternatives have limited diagnostic accuracy for the identification of coronary vascular dysfunction in patients with INOCA, and a regular coronary angiography and/or coronary computed tomography scan cannot establish the diagnosis. CONCLUSIONS: A complete CFT, including acetylcholine and adenosine tests, should be considered in patients with INOCA.

Ischaemia with no obstructive coronary arteries.

Ischaemia with no obstructive coronary arteries (INOCA) is a common ischaemic heart disease with a female preponderance, mostly due to underlying coronary vascular dysfunction comprising coronary microvascular dysfunction and/or epicardial coronary vasospasm. Since standard ischaemia detection tests and coronary angiograms are not suitable to diagnose coronary vascular dysfunction, INOCA is often overlooked in current cardiology practice. Future research, including large outcome trials, is much awaited. Yet, adequate diagnosis is possible and treatment options are available and vital to reduce symptoms and most probably improve cardiovascular prognosis. This review intends to give a brief overview of the clinical presentation, underlying pathophysiology, and the diagnostic and treatment options in patients with suspected INOCA.

Psychological and clinical characteristics of female patients with spontaneous coronary artery dissection.

AIMS: Spontaneous coronary artery dissection (SCAD) is increasingly recognised as a cause of myocardial infarction, but psychological characteristics of patients with SCAD have not yet been extensively investigated. We assessed the prevalence of a broad range of psychological and clinical factors, and their inter-relationships in patients with a history of SCAD. Furthermore, we investigated whether specific clusters of patients with SCAD can be identified. METHODS: Participants were recruited between March and May 2019 from a Dutch SCAD database and completed online questionnaires. Clinical information was verified by review of medical records. Participants were predominantly female (172/183; 94%). Analyses focused on the 172 female patients (mean age 52.0 ± 7.5 years, 37% postmenopausal). RESULTS: The most common comorbidities of SCAD were migraine (52%), fibromuscular dysplasia (FMD; 29%), chronic pain (29%), and tinnitus (28%). Six women (3%) had pregnancy-associated SCAD. Traditional cardiovascular risk factors were rare (<10%), except for hypertension (31%). Psychological assessment indicated high levels of perceived stress (PSS-10 ≥14; 50%), fatigue (FAS-10 ≥22; 56%), and a frequent history of burnout (25%). The prevalence of depression (9%) and anxiety (12%) was relatively low. Three clusters were identified: (A) FMD and chronic non-ischaemic conditions (tinnitus, chronic pain, and irritable bowel syndrome); (B) migraine; and (C) none of these conditions. CONCLUSION: This study shows that perceived stress and fatigue are common in patients with SCAD, in addition to prevalent comorbid FMD, migraine, tinnitus, and non-ischaemic pain conditions. These factors may add to developing tailored rehabilitation programmes for patients with SCAD.

Spontaneous coronary artery dissections and associated predisposing factors: a narrative review.

Spontaneous coronary artery dissection (SCAD) represents around 25% of cases of acute coronary syndromes (ACS) in women aged 40-65 years who have few or no traditional cardiovascular risk factors. It is assumed that the incidence is underestimated, as the angiographic appearance of SCAD may often mimic atherosclerosis. This review aims to examine SCAD by focusing on the associated predisposing factors and precipitating stressors in this heterogeneous patient population, as well as the best treatment approach and the prognosis. Progressive knowledge has improved our current understanding of SCAD, but more awareness among clinicians is necessary. Recently, two position papers from the European Society of Cardiology (ESC) and the American Heart Association (AHA) have been released, which will be summarised in brief.

Similar pro-NT and pro-RLX2 levels after preeclampsia and after uncomplicated pregnancy.

OBJECTIVE: Women are at increased risk of developing cardiovascular disease (CVD) after preeclampsia. Proneurotensin 1-117 (pro-NT) and prorelaxin 2 connecting peptide (pro-RLX2) have recently emerged as potential biomarkers for CVD risk in women. We assessed pro-NT and pro-RLX2 levels in women with and without a history of preeclampsia. STUDY DESIGN: 339 women with a history of early-onset preeclampsia and 327 women with an uncomplicated pregnancy underwent cardiovascular screening 10 years after delivery (the Preeclampsia Risk EValuation in FEMales (PREVFEM) cohort). MAIN OUTCOME MEASURES: Pro-NT, a stable fragment of the neurotensin precursor, was assessed in the whole cohort. Pro-RLX2, the stable connecting peptide of the relaxin 2 prohormone, was assessed in a subset of this cohort, consisting of 27 women with a history of preeclampsia and 23 healthy controls. Associations between biomarker levels and traditional CVD risk factors in the preeclampsia and control group were assessed by Pearson's correlation coefficient. RESULTS: We found no differences in pro-NT and pro-RLX2 levels between the preeclampsia and control group. Pro-NT levels were associated with higher HbA1c levels (r=0.113, p-value 0.045) and with BMI (r=0.124, p-value 0.027), but only in the control group. Pro-RLX2 was related to current smoking and triglyceride levels in women with a history of preeclampsia and related to LDL-cholesterol in women with an uncomplicated pregnancy. CONCLUSIONS: Pro-NT and pro-RLX2 levels were comparable in women 10 years after preeclampsia and women with an uncomplicated pregnancy. The role of pro-NT and pro-RLX2 in CVD development after preeclampsia should be further investigated.

Long-term cardiovascular health in adult cancer survivors.

The number of cancer survivors has tremendously increased over the past decades as a result of aging of the population and improvements in early cancer detection and treatment. Ongoing successes in cancer treatment are expected to result in a further increase in the number of long-term survivors. However, cancer treatment can have detrimental cardiovascular side-effects that impact morbidity and mortality, reducing quality of life in cancer survivors. The spectrum of radiotherapy- and chemotherapy-induced cardiovascular disease is broad, varying from subclinical valvular dysfunction to overt congestive heart failure, and such effects may not be apparent for more than twenty years after the initial cancer treatment. Awareness of these long-term side-effects is of crucial value in the management of these patients, in order to reduce the impact of cardiovascular morbidity and mortality. This review provides a comprehensive overview of the long-term cardiovascular complications of cancer treatments (radiotherapy and chemotherapy) in adult cancer survivors.

['Red yeast rice' as a cholesterol-lowering substance?Caution is warranted]. / 'Rode gist rijst' als cholesterolverlager?

- In various non-medical publications, red yeast rice (red fermented rice, RYR) is recommended as a cholesterol-lowering substance. This supplement contains a naturally occurring statin, namely monacolin K.- Patients who wish to use RYR should be advised to only take products from reputable pharmaceutical companies. Pharmacists can provide advice on this.- Users of RYR should be alerted to the potential drug interactions and serious risks associated with its use during pregnancy.- RYR appears to be better tolerated than statins. This difference in tolerance can be traced back to the applied dosages. On average, the daily RYR dosage contains less statin than the standard dosage for statins.- The Netherlands Food and Consumer Product Safety Authority should urgently test the RYR supplements available in the Netherlands to gain more insight into the quality of said products.- Mandatory registration of RYR as an herbal medicine appears necessary to guarantee the quality of, and monacolin levels in, the products and to reduce health risks.

Diagnosis of takotsubo cardiomyopathy is increasing over time in patients presenting as ST-elevation myocardial infarction.

BACKGROUND: Takotsubo cardiomyopathy often presents with the clinical signs of ST-elevation myocardial infarction (STEMI). The increase in scientific publications addressing this relatively rare condition may result in higher awareness and diagnosis of takotsubo cardiomyopathy. AIM: To assess the observed prevalence per year of takotsubo cardiomyopathy in a large registry of patients with STEMI, during a 12-year inclusion period. METHOD: All patients presenting with STEMI at a large regional cardiology clinic were entered into a database (n = 8,413, mean age 63 ± 13 years). Takotsubo cardiomyopathy was diagnosed in 42 patients (0.5 %). Years of evaluation were defined as 'early years' (January 2002 to December 2007; n = 4350) and 'later years' (January 2008 to December 2013). Multivariable analyses were performed to adjust for differences in demographical and clinical variables. RESULTS: In later years, the age of STEMI patients was slightly higher (64 ± 13 vs. 63 ± 13 years, p < 0.001), with more patients with clinical symptoms of shock (10 vs. 7 %, p < 0.001) or a history of percutaneous coronary intervention or hypertension (10 vs. 8 %, p = 0.001 and 37 vs. 34 %, p < 0.001). Smoking and a positive family history were less often observed during later years (39 vs. 46 %, p < 0.001 and 37 vs. 42 % p < 0.001). Patients with takotsubo cardiomyopathy were more often female (81 vs. 27 %, p = 0.001). Takotsubo cardiomyopathy was more often diagnosed in the later period (0.7 vs. 0.3 %, OR 2.4, 95 % CI 1.2-4.6, p = 0.009). The higher prevalence of takotsubo cardiomyopathy in recent years remained significant after adjustment for differences in patient characteristics (OR 2.1, 95 % CI 1.1-4.3). CONCLUSION: Takotsubo cardiomyopathy is currently more often diagnosed in patients with STEMI compared with in earlier years. This is probably due to the increased scientific and clinical awareness among doctors, but the prevalence is still low.

Cardiovascular risk of BRCA1/2 mutation carriers: A review.

BRCA1/2 mutation carriers are at high risk of breast and ovarian cancer. The number of studies on non-cancer endpoints in BRCA1/2 mutation carriers is still limited. BRCA1/2 mutation carriers may be at higher cardiovascular risk due to early menopause after risk-reducing salpingo-oophorectomy and/or due to the potential cardiotoxic effects of breast cancer treatment (radiotherapy and chemotherapy). Moreover, BRCA genes have a role as a gatekeeper in cardiac function and structure, which may affect susceptibility to cardiac damage. Our goal is to review current knowledge of cardiovascular risk among BRCA1/2 mutation carriers.

Does diastolic dysfunction precede systolic dysfunction in trastuzumab-induced cardiotoxicity? Assessment with multigated radionuclide angiography (MUGA).

BACKGROUND: Trastuzumab is successfully used for the treatment of HER2-positive breast cancer. Because of its association with cardiotoxicity, LVEF is monitored by MUGA, though this is a relatively late measure of cardiac function. Diastolic dysfunction (DD) is believed to be an early predictor of cardiac impairment. We evaluate the merit of MUGA-derived diastolic function parameters in the early detection of trastuzumab-induced cardiotoxicity (TIC). METHODS AND RESULTS: 77 trastuzumab-treated patients with normal baseline systolic and diastolic function were retrospectively selected (n = 77). All serial MUGA examinations were re-analyzed for systolic and diastolic function parameters. 36 patients (47%) developed SD and 45 patients (58%) DD during treatment. Both systolic and diastolic parameters significantly decreased. Of the patients with SD, 24 (67%) also developed DD. DD developed prior to systolic impairment in 54% of cases, in 42% vice versa, while time to occurrence did not differ significantly (P = .52). This also applied to the subgroup of advanced stage breast cancer patients (P = .1). CONCLUSIONS: Trastzumab-induced SD and DD can be detected by MUGA. An impairment of MUGA-derived diastolic parameters does not occur prior to SD and therefore cannot be used as earlier predictors of TIC.

Yearly hypertension screening in women with a history of pre-eclampsia: a cost-effectiveness analysis.

BACKGROUND: Women with a history of preeclampsia are at increased risk for future hypertension and cardiovascular disease (CVD); until now it is not clear whether preventive measures are needed. METHODS: A decision-analytic Markov model was constructed to evaluate healthcare costs and effects of screening and treatment (100 % compliance) for hypertension post preeclampsia based on the available literature. Cardiovascular events and CVD mortality were defined as health states. Outcomes were measured in absolute costs, events, life-years and quality-adjusted life-years (QALYs). Sensitivity and threshold analyses were performed to address uncertainty. RESULTS: Over a 20-year time horizon, events occurred in 7.2 % of the population after screening, and in 8.5 % of the population without screening. QALYs increased from 16.37 (no screening strategy) to 16.40 (screening strategy), an increment of 0.03 (95 % CI 0.01;0.05) QALYs. Total expected costs were € 8016 in the screening strategy, and € 9087 in the none screening strategy (expected saving of € 1071 (95 % CI - 3146;-87) per person). CONCLUSION: Annual hypertension screening and treatment in women with a history of preeclampsia may save costs, for at least a similar quality of life and survival due to prevented CVD compared with standard care.

BRCA1/2 mutation carriers are potentially at higher cardiovascular risk.

BRCA1/2 mutation carriers have an elevated risk of developing breast and ovarian cancer at a relatively young age. Risk-reducing salpingo-oophorectomy is an established strategy to tremendously reduce the risk of ovarian cancer. It is recommended to perform this surgery at age 35-40 years (BRCA1) and at age 40-45 years (BRCA2) resulting in an early and abrupt menopause. BRCA1/2 mutation carriers are potentially at higher risk of cardiovascular diseases due to early surgical menopause, and cardiotoxic effects of adjuvant treatment for breast cancer. Furthermore, preliminary results of experimental studies suggest a possible causative function of the BRCA genes in cardiovascular risk. More research on cardiovascular health risks in BRCA1/2 mutation carriers is needed, especially in the field of cardio-oncology, requiring additional attention to potentially cumulative effects on cardiovascular risks in this specific group of women.

Serum AMH levels in women with a history of preeclampsia suggest a role for vascular factors in ovarian aging.

CONTEXT: The association between early menopause and vascular disease as a possible causative factor has recently received attention. Preeclampsia (PE) is associated with future cardiovascular risk factors, and this premature vascular aging potentially modifies the ovarian aging process. OBJECTIVE: The purpose of this study was to assess whether women with a history of PE have lower anti-Müllerian hormone (AMH) levels than women with normotensive pregnancies. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted in a tertiary referral center. PATIENTS: Clinical data and blood samples of participants in the Preeclampsia Risk EValuation in FEMales study were used (336 women with a history of PE and 329 women after a normotensive pregnancy). INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: The relative decrease in AMH levels was assessed after a median follow-up of 10.5 years. RESULTS: The mean AMH level was 2.00 ± 1.87 µg/L in the PE group compared with 2.26 ± 2.56 µg/L in the reference group. Linear regression analysis with censoring for undetectable AMH levels, adjusted for age, smoking, and hormonal contraceptive use, showed a relative reduction in AMH levels of 20.9% at any age (fold change 0.79, 95% confidence interval, 0.67-0.94). CONCLUSIONS: We demonstrate that women with a history of PE have significantly lower AMH levels than women with normotensive pregnancies. Calculations based on a reference population indicate advancement of reproductive age of approximately 1.5 years. Because PE is considered a manifestation of impaired vascular health, these results support the hypothesis that compromised vascular health could act as a causative mechanism in early ovarian aging.

Longitudinal analysis of cardiovascular risk parameters in women with a history of hypertensive pregnancy disorders: the Doetinchem Cohort Study.

OBJECTIVE: Women with hypertensive pregnancy disorders (HPD) are at increased risk of developing hypertension and cardiovascular disease later in life; however, it is not known how cardiovascular risk develops throughout life. We evaluated the longitudinal trends in cardiovascular risk factors in women after hypertensive pregnancy disorders compared with women with normotensive pregnancies. DESIGN AND POPULATION: All women of the Doetinchem Cohort Study (1987-91), a population-based cohort study, were included. METHODS: Women were examined (questionnaires and physical examination) four times at 5-year intervals. History of HPD was assessed from questionnaires. We compared 5-year changes in risk factors between women with and without HPD, by analysing longitudinal trends using generalised estimating equation analysis to estimate the effects of HPD and mean age, adjusting for treatment, body mass index (BMI), smoking and socio-economic status. MAIN OUTCOME MEASURES: Change over time in traditional cardiovascular risk factors, including systolic blood pressure (SBP) and diastolic blood pressure (DBP), BMI, total and high-density lipoprotein (HDL) cholesterol for women with and without a history of HPD. RESULTS: A total of 2703 women with normotensive pregnancies (mean age 40.5 years, SD 10.4) and 689 women with a history of HPD (mean age 38.4 years, SD 9.5) were included. Compared with normotensive women, in women with a history of HPD, SBP was 2.8 mmHg higher (95% CI 1.7-3.9), DBP was 2.3 mmHg higher (95% CI 1.6-3.0) and BMI was 0.7 kg/m(2) higher (95% CI 0.4-1.1). Total cholesterol (-0.05; 95% CI -0.1 to 0.0) and HDL cholesterol (0.02; 95% CI -0.0 to 0.1) were similar in both groups. No difference in annual change in blood pressure or in the other risk factors was observed between women with and without a history of HPD. CONCLUSION: Women with a history of HPD have higher levels of SBP, DBP and BMI compared with normotensive women, but the increase with ageing is similar in both groups.

Sex-Based Differences in Cardiac Arrhythmias, ICD Utilisation and Cardiac Resynchronisation Therapy.

Many important differences in the presentation and clinical course of cardiac arrhythmias are present between men and women that should be accounted for in clinical practice. In this paper, we review published data on gender differences in cardiac excitable properties, supraventricular tachycardias, ventricular tachycardias, sudden cardiac death, and the utilisation of implantable defibrillators and cardiac resynchronisation therapy. Women have a higher heart rate at rest, and a longer QT interval than men. They further have a narrower QRS complex and lower QRS voltages on the 12-lead ECG with more often non-specific repolarisation abnormalities at rest. Supraventricular tachycardias, such as AV nodal reentrant tachycardia, are twice as frequent in women compared with men. Atrial fibrillation, however, has a 1.5-fold higher prevalence in men. The triggers for idiopathic right ventricular outflow tract tachycardia (VT) initiation are gender specific, i.e. hormonal changes play an important role in the occurrence of these VTs in women. There are clear-cut gender differences in acquired and congenital LQTS. Brugada syndrome affects men more commonly and severely than women. Sudden cardiac death is less prevalent in women at all ages and occurs 10 years later in women than in men. This may be related to the later onset of clinically manifest coronary heart disease in women. Among patients who receive ICDs and CRT devices, women appear to be under-represented, while they may benefit even more from these novel therapies.

Gender differences in coronary heart disease.

Cardiovascular disease develops 7 to 10 years later in women than in men and is still the major cause of death in women. The risk of heart disease in women is often underestimated due to the misperception that females are 'protected' against cardiovascular disease. The under-recognition of heart disease and differences in clinical presentation in women lead to less aggressive treatment strategies and a lower representation of women in clinical trials. Furthermore, self-awareness in women and identification of their cardiovascular risk factors needs more attention, which should result in a better prevention of cardiovascular events. In this review we summarise the major issues that are important in the diagnosis and treatment of coronary heart disease in women. (Neth Heart J 2010;18:598-603.).

Women's health in menopause with a focus on hypertension.

In menopause transition many women have vasomotor symptoms which may affect their normal daily activities. With the decline in oestrogen levels, risk factors for coronary heart disease (CHD) become more apparent, especially hypertension. The onset of hypertension can cause a variety of complaints that are often attributed to the menopause. Risk factor identification is poorly managed in middle-aged women and should be the first step in the evaluation and treatment of women with perimenopausal symptoms. In women at low risk for CHD, there is still a window of opportunity for safe hormone prescription in the first years proximal to menopause. (Neth Heart J 2009;17:68-72.).