Cardiovascular disease (CVD) accounts for more deaths in women than breast cancer, lung cancer and chronic lung disease combined, with a comparable mortality to that of men. Many women and physicians do not identify CVD as a major morbidity and mortality in women, resulting in significant delays in diagnosis and treatment. While advances have been made in the diagnosis, treatment and outcomes of CVD in women, there often remains insufficient evidence to guide effective, lifesaving care of women. This review of sex-specific and traditional CVD risk and risk-enhancing factors in women identifies areas of knowledge gaps to consider for investigation. A focus on the coronary vasculature reveals physiological differences of clinical relevance which can be interrogated. Inspection of and addressing disadvantage and gender bias in both the medical and lay communities should continue to be addressed. As CVD results from traditional risk factors and emerging risk-enhancing factors, a focus on the detection of preclinical cardiovascular disease may be of particular importance for women. Unique risk markers originate early in pre-menopausal women, as this is considered a healthy period of life. Awareness and implementation of the existing knowledge of sex-specific risk factors and sex-specific thresholds to educate women and physicians are needed. The anticipated life course of women supports a broadening focus on CVD toward that of lifelong care and emphasize key transitional stages for women—early risk factor onset, pregnancy, menopausal transition, and so on. This review is a call to action to re-envision a health system approach for lifespan prevention, detection, and treatment pathways to reduce CVD risk in women.

BACKGROUND: Coronary vasomotor dysfunction is diagnosed by a coronary function testing (CFT). However, protocols vary, and the influence of access site and concomitant vasodilator medication on the diagnostic yield and safety of CFT is unclear. This study assessed the diagnostic yield and safety of CFT by radial access with intraarterial calcium channel blockers compared with CFT by femoral access. METHODS: Data were obtained from the Netherlands Registry of Invasive Coronary Vasomotor Function Testing, a Dutch multicenter collaboration on CFT. Patients who underwent CFT between December 2020 and July 2025 were included. RESULTS: A total of 1885 patients were included, 1436 (76.2%) with primary radial access and 380 (20.2%) with primary femoral access. In 69 (3.7%) patients conversion from radial to femoral access was necessary. The conversion group was analyzed separately. The total diagnostic yield of coronary vasomotor dysfunction was 78.5%. There was no significant difference in the prevalence of coronary vasomotor dysfunction between patients with primary radial versus femoral access (79.2% versus 75.3%; P =0.1). There was also no difference in total diagnostic yield between the group without conversion and the conversion group (78.4% versus 82.6%; P =0.4); however, spasm was more prevalent in the conversion group (67.7% versus 79.4%; P =0.04). There were no differences in CFT complication rates between groups. CONCLUSIONS: Primary radial access with routine administration of calcium channel blockers was not associated with a lower diagnostic yield in CFT than primary femoral access. Procedural safety was comparable.

BACKGROUND:Coronary vasospasm is highly prevalent in patients with angina and no obstructive coronary arteries (ANOCA). A central mechanism of vasospasm in these patients arises from endothelial dysfunction and smooth muscle hyper-reactivity that disrupt the nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate pathway governing vasodilation. Vericiguat, an sGC stimulator that enhances sGC sensitivity to nitric oxide, may therefore be a therapeutic option for patients with coronary vasospasm. OBJECTIVES:To evaluate the effects of vericiguat on angina symptoms, endothelial function, peripheral microvascular vasodilator responses, and safety in ANOCA patients with epicardial and/or microvascular vasospasm. METHODS:In this double-blind, placebo-controlled, randomized crossover trial, patients were randomized 1:1 to vericiguat followed by placebo, or placebo followed by vericiguat. Each treatment period lasted 10 weeks. The primary functional outcome was the difference in peripheral vasodilator function during acetylcholine iontophoresis using laser speckle contrast imaging; the primary symptom outcome was the difference in daily angina episodes, recorded via the ORBITA-app, between treatments. RESULTS:Among the 57 patients enrolled in the trial, the median age was 55 years [50, 61], and 44 (77%) were female. Vericiguat did not improve peripheral vasodilator function, assessed by LASCA during acetylcholine iontophoresis, compared with placebo on AUC (intervention effect estimate -1221 APU•s, 95% CI -4237 to 1796, p=0.42). For the primary symptom endpoint, the final-day odds ratio for reduction in angina episodes recorded via the ORBITA-app, the posterior was distributed more towards the direction favoring placebo (OR 0.84, 95% CrI 0.65 to 1.04); however, it did not meet the prespecified efficacy or harm criterion (posterior probability of benefit with vericiguat versus placebo 0.07).; episode counts and angina-free days over 70 days were similar between arms. Vericiguat was generally tolerated, with modest reductions in blood pressure, no clinically relevant laboratory abnormalities, and no treatment-related serious adverse events. CONCLUSIONS:The Vericiguat in Vasospastic Angina trial did not demonstrate evidence of improved peripheral vasodilator function or anginal symptoms in patients with coronary vasospasm. Vericiguat was nonetheless generally tolerated, with no treatment-related serious adverse events. Larger studies with longer treatment exposure could further evaluate the potential clinical effects of vericiguat in patients with coronary vasospasm.

The use of extracorporeal cardiopulmonary resuscitation (ECPR) is emerging. In cardiac arrest patients with return of spontaneous circulation (ROSC), the electrocardiogram (ECG) guides the need for immediate coronary angiography (CAG). In ECPR patients, the diagnostic value of the ECG and the role of CAG remain unclear. This single-centre, retrospective study included all adult ECPR patients admitted to Amsterdam UMC (2018–2024). ECPR was defined as cannulation on venoarterial extracorporeal membrane oxygenation during ongoing continuous or intermittent resuscitation, before sustained ROSC (≥ 20 min). The primary outcome included the presence and extent of coronary artery disease (CAD). Logistic regression was used to identify predictors of undergoing CAG and having a culprit. The impact of CAG on survival was assessed using Cox proportional hazard models and Kaplan-Meier curves. Ninety-two patients (mean age of 53 years, 65

BACKGROUND:Coronary vasospasm is highly prevalent in patients with angina and no obstructive coronary arteries (ANOCA). In the pathophysiology of coronary vasospasm, endothelial dysfunction and vascular smooth muscle cell hyperreactivity may cause an imbalance between vasodilation and vasoconstriction. Within this pathophysiology, nitric oxide is crucial. Nitric oxide activates soluble guanylate cyclase, which through the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, reduces intracellular calcium levels in vascular smooth muscle cells, resulting in vasodilation. sGC stimulators, such as vericiguat, enhance the sensitivity of soluble guanylate cyclase to nitric oxide. Vericiguat was shown to be well tolerated, safe, and clinically effective in both heart failure patients as well as in patients with coronary artery disease. We hypothesize that vericiguat restores the balance between vasodilation and vasoconstriction and thereby reduces coronary spasm episodes in ANOCA patients. METHODS:In the Vericiguat in Vasospastic Angina trial, we will assess the impact of vericiguat on endothelial function and microvascular vasodilator responses, angina and quality of life. Additionally, we will evaluate the tolerability and safety of vericiguat in patients with coronary vasospasm as the pathophysiological substrate of ANOCA. 50 patients will be included in the trial, and will be randomized in a 1:1 ratio to placebo treatment first, followed by vericiguat treatment, or vericiguat treatment first, followed by placebo treatment. TRIAL REGISTRATION:The Vericiguat in Vasospastic Angina trial is registered at ClinicalTrials.gov ID NCT06415227.

BACKGROUND:Few studies examined treatment-specific long-term risks of cardiovascular diseases (CVD) in diffuse large B-cell lymphoma survivors treated with potentially cardiotoxic radiotherapy and/or chemotherapy with or without rituximab after the 1990s. METHODS:Long-term CVD risk was examined in a multicenter cohort comprising 2356 diffuse large B-cell lymphoma survivors who survived at least 5 years and who were treated at ages 15-61 years in 1989-2012. CVD data were acquired from medical records, general practitioners, and disease registries. Observed CVD numbers were compared with expected CVD incidence in the Dutch population to estimate standardized incidence ratios (SIRs) and absolute excess risks (10 000 person-years). Treatment-specific CVD risks were assessed using multivariable Cox regression. RESULTS:During a median follow-up of 14.2 years (IQR = 10.1-18.9 years), 312 survivors were diagnosed with a first CVD at least 5 years after treatment. Compared with the general population, diffuse large B-cell lymphoma survivors had increased risks of heart failure ([HF]; SIR = 3.9, 95% confidence interval [CI] = 3.4 to 4.6; absolute excess risk = 62.8) and cerebrovascular accident (SIR = 1.3, 95% CI = 1.0 to 1.7; absolute excess risk = 9.8), while risk of coronary artery disease was decreased (SIR = 0.7, 95% CI = 0.5 to 0.9; absolute excess risk = -30.9). HF risk was higher among females (SIR = 5.3, 95% CI = 4.2 to 6.5) than males (SIR = 3.2, 95% CI = 2.6 to 4.0, P for heterogeneity < .001), and among survivors aged 40 years and younger at diffuse large B-cell lymphoma treatment (SIR = 10.5, 95% CI = 7.2 to 14.8; P for trend < .001). Exposure to more than 300 mg/m2 doxorubicin was associated with a 2.8-fold (95% CI = 1.7 to 4.5) increased risk of cardiomyopathy or HF, while radiotherapy involving the heart was associated with a 1.9-fold (95% CI = 1.1 to 3.1) increased risk of valvular heart disease. CONCLUSION:Those surviving at least 5 years after diffuse large B-cell lymphoma have increased risks of developing CVDs, especially HF. Physicians and patients should recognize this risk, and individualized cardiac screening should be considered.

BACKGROUND AND AIMS:Women remain underrepresented in heart failure (HF) trials, raising concerns about potential undetected sex-specific differences in treatment efficacy. This study assesses sex differences in the primary efficacy endpoint of HF treatments and examines whether the proportion of women enrolled in a trial influences (variations in) treatment effect estimates. METHODS:A systematic search was conducted up to 21 March 2025, including randomized controlled trials (RCTs) (≥100 patients) evaluating pharmacological HF treatments vs. placebo or usual care, with clinical events as the primary outcome. Sex differences in the primary outcome were assessed using a random-effects meta-analysis of the reported relative effect measures (REM) and pooled estimates. For key clinical outcomes, meta-regression analyses were performed to examine the association between the proportion of women enrolled and sex differences in REMs, as well as the overall REMs without separating sex. RESULTS:Of 5749 screened publications, 139 RCTs met inclusion criteria, with 292 027 patients (28.1% women). Based on 78 RCTs that reported sex-stratified treatment effects, pooled analysis showed no difference in treatment efficacy between women and men (delta ln[REM] 0.00; 95% confidence interval (CI) -0.04 to 0.03; P = .85; I2 = 4.1%). Meta-regression found no association between the proportion of women and sex differences in REM (78 RCTs, P = .25), overall efficacy (139 RCTs, P = .24), or other clinical outcomes. CONCLUSIONS:These findings suggest that pharmacological efficacy in HF does not differ by sex and that historical female underrepresentation in trials is unlikely to have masked important sex differences. Nonetheless, improving sex balance in HF trials remains essential for societal and ethical reasons.

Cardiovascular disease is the leading cause of death in women, yet significant disparities persist in diagnosis, treatment, and research representation. This clinical consensus statement outlines the rationale and framework for establishing women's heart centres (WHCs) in Europe. Women's heart centres are proposed as hub-and-spoke reference networks embedded within existing cardiovascular systems, delivering multidisciplinary, sex-sensitive care across the life course. The document defines referral pathways, operational standards, and core and advanced training competencies in women's cardiovascular health. Key domains include ischaemia/myocardial infarction with non-obstructive coronary arteries, cardio-obstetrics, cardio-oncology, autoimmune disease, mental health, and cardiac rehabilitation. Implementation strategies emphasize scalable models, integration with primary care, telemedicine, quality improvement, and research engagement. Although long-term outcome data remain limited, available evidence suggests improved diagnostic precision, risk factor control, and patient-reported outcomes. Establishing WHC offers a structured approach to reduce inequities and strengthen cardiovascular care for women across Europe.

BACKGROUND AND AIMS:Cardiovascular disease is the leading cause of death among women, yet women remain underrepresented in cardiovascular clinical trials. This qualitative study explored perspectives of research personnel on barriers and facilitators to female trial participation. METHODS:Semi-structured interviews were conducted between June and September 2024 across cardiology research sites in the Netherlands. Twenty research professionals (70% women), including nurses, trial coordinators, and cardiologists/principal investigators, were interviewed using a predefined topic guide. Interviews were transcribed verbatim and analyzed using thematic content analysis. RESULTS:Data saturation, defined as the point at which no new themes emerged from additional interviews, was reached after 20 interviews. Three main themes emerged: (1) the importance of diversity in trials, (2) barriers to participation, and (3) facilitators for participation. Although diversity was widely recognized as essential, it was also perceived as challenging to achieve. Key barriers to women's participation included (1) distrust in research, (2) fear of medication side effects, (3) not meeting inclusion criteria, (4) and caregiving responsibilities or limited time. Mentioned facilitators were grouped into two categories: (1) manner of approach, emphasizing tailored and patient-centered recruitment strategies, and (2) study design adjustments, including fixed ratios of females, female-only trials, and improved logistical flexibility. CONCLUSIONS:Research personnel distinguished between women unable to participate due to external constraints and those unwilling due to personal beliefs. Addressing trust, perceived risks, and logistical challenges through tailored recruitment and adapted trial designs may enhance women's participation in cardiovascular clinical trials.

In patients who have angina with non-obstructive coronary artery disease (ANOCA), invasive coronary function testing (ICFT) is the gold standard to comprehensively diagnose coronary dysfunction. Coronary dysfunction is divided into the endotypes coronary vasospasm, coronary endothelial dysfunction, and coronary microvascular dysfunction (i.e., an abnormal reduced coronary flow reserve [CFR] and/or enhanced microvascular resistance [MR]). However, because of the inherently invasive nature of ICFT, it is important to investigate non-invasive approaches for the diagnosis of coronary dysfunction. Several non-invasive modalities have been proposed as alternative techniques to measure different endotypes of coronary dysfunction. This is promising, given their higher availability and easier applicability. As such, an important clinical question is whether these non-invasive methods are equivalent to invasive tests. In this review, we provide an overview of the invasive and non-invasive diagnostic modalities available to assess coronary dysfunction. Our findings indicate that only CFR can be reliably measured non-invasively, using positron emission tomography (PET), transthoracic Doppler echocardiography (TTDE), and possibly stress cardiac magnetic resonance (CMR) imaging, although the latter has shown conflicting results. Reliable non-invasive techniques to measure coronary vasospasm, coronary endothelial dysfunction, or MR are scarce. Since most patients suffer from more than one coronary dysfunction entity, the added value of non-invasive techniques is still limited. To date, ICFT is the only method capable of investigating all endotypes of coronary dysfunction. Studies investigating the performance of non-invasive modalities for the diagnosis of all components of coronary dysfunction in ANOCA patients are warranted.

AIMS:Female underrepresentation in clinical trials of acute coronary syndromes (ACS) may hinder the assessment of sex-based differences in the outcomes of long-term pharmacological therapy. The presence of these differences and their potential association with female representation in clinical trials remain unclear. METHODS AND RESULTS:A systematic search of Embase, Medline Ovid, and Cochrane Central was conducted through 1 July 2025, in accordance with the reporting standards of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eligible randomized controlled trials (RCTs) compared long-term pharmacological therapy for ACS with placebo or standard care, included ≥1-year follow-up, and reported a clinical event as the primary outcome. Sex differences in treatment effects were analysed using a random-effects meta-analysis, while meta-regression was used to assess the association between the proportion of females in each trial and these differences. The main outcome was the sex difference in the relative effect measure (REM; mostly a hazard ratio) for the primary efficacy endpoint. Among 102 RCTs, female representation ranged from 10 to 52%. Forty-eight trials provided sex-stratified data. Pooled analysis showed no evidence of sex-related differences in efficacy: the mean difference in the log of the REM of males minus females was 0.00 (95% confidence interval, -0.05-0.05; P = 0.98; heterogeneity I² = 0%). Meta-regression indicated no relationship between female trial participation and sex-specific treatment effects. CONCLUSION:In RCTs of long-term pharmacological therapy after ACS, treatment efficacy was comparable between sexes, irrespective of sex distribution. These findings support current guidelines recommending equivalent long-term pharmacological strategies for secondary prevention in both sexes.

Aims:This study reports sex differences in the clinical presentation, treatment management and outcomes of patients with acute coronary syndrome (ACS) in The Netherlands, using data from the FORCE-ACS registry. Methods:A prospective analysis was conducted using data from 5023 patients admitted with ACS between 2015 and 2019, with complete three-year follow-up. Demographic data, clinical characteristics, in-hospital treatment and outcomes were compared by sex. Multivariable regression analyses explored associations between sex and clinical outcomes. Results:Of the 5023 patients, 29 % were women. Women were generally older, with a significantly higher prevalence of hypertension (61.7 % vs 54.2 %), chronic kidney disease (25.7 % vs. 18.5 %) and myocardial infarction with non-obstructive coronary arteries (MINOCA) (13.5 % vs. 6.5 %). Women less frequently underwent revascularisation, even after excluding those with non-obstructive coronary artery disease, and received less medical treatment compared to their male counterparts. At 36 months, women had higher unadjusted mortality rate (13.7 % vs. 11.0 %, OR 1.28, 95 % CI: 1.07-1.54) and bleeding events (26.2 % vs. 22.3 %, OR 1.24, 95 % CI: 1.08-1.43). However, after adjustment for age and baseline characteristics, these differences were no longer statistically significant. Recurrent ACS and stroke remained similar in both groups, also after correction. Conclusion:Differences between women and men were observed in clinical presentation, interventional treatment, pharmacotherapy and outcomes among ACS patients in The Netherlands. Despite receiving less guideline-recommended care, women had similar adjusted 36-month outcomes as men. These findings show that there is room for improvement in the management of ACS, with a focus on optimized treatment strategies for women.

Spontaneous coronary artery dissection (SCAD) occurs in 1–4

Background Prior studies showed underrepresentation of females in cardiovascular disease (CVD) clinical trials, potentially hindering accurate treatment effect estimates. We assessed the female contribution to treatment effect estimates in selected CVD trials and explored sex differences in efficacy outcomes. Methods We analyzed completed (1997–2024) randomized controlled CVD trials performed via the Dutch WCN Investigator Network. Female participation was quantified using the Participation to Prevalence (in the population) Ratio (PPR F ). In trials with a cardiovascular event as the primary efficacy endpoint, a meta-analysis was conducted to evaluate differences in treatment effect on the study-specific primary endpoint between females and males using a random-effects model. Results In 115 trials investigating various treatments across different cardiovascular domains (801 k participants, 29.1% females), the median PPR F was 0.75 (interquartile range: 0.64–0.83), while 58% of trials had a PPR F below 0.8 (underrepresentation). Based on 46 trials, female contribution to primary endpoints was lower than their sample size contribution (mean 26.2% versus 28.5%). Similarly, based on 66 trials, female contribution to sex-stratified efficacy estimates was lower than their sample size contribution (27.4% versus 29.2%). Regarding the primary endpoint, the relative treatment effect was similar in females and males: pooled difference of the relative effect measure on the natural log scale of −0.02, 95% CI −0.05 to 0.01, p = 0.23, I 2 = 11%. Conclusion Despite underrepresentation, female participation in the selected WCN-CVD trials was sufficient to exclude major sex differences in efficacy. Given the limited and heterogeneous trial sample, further disease-specific studies are needed, and greater female inclusion remains essential for equity and safety insights.

BACKGROUND:Angina with nonobstructive coronary arteries (ANOCA) is a major cause of chronic coronary syndromes, affecting nearly half of patients with anginal symptoms who undergo invasive coronary angiography. ANOCA may lead to substantial symptom burden, increased risk of adverse cardiac events, increased healthcare utilization due to ongoing symptoms, repeat hospitalizations, and invasive testing. The pathophysiology of ANOCA often involves a variety of coronary disorders, such as coronary microvascular dysfunction, epicardial or microvascular vasospasm and endothelial dysfunction. While coronary function testing (CFT) can identify each of these specific endotypes, in current practice it is used as a second- or third-line diagnostic tool, delaying diagnosis which contributes to persistent symptoms and diminished quality of life. The ILIAS ANOCA clinical trial aims to enhance understanding and management of ANOCA through early routine CFT-guided management. METHODS:After exclusion of obstructive coronary artery disease, eligible patients undergo comprehensive CFT, and will be randomized to blinding of the CFT results (control group) or disclosure of the CFT results combined with a tailored medical therapy escalation plan (intervention group). The control group will be unblinded after 1 year. The primary outcome is the mean difference in the within-subject change in Seattle Angina Questionnaire (SAQ) summary score between the groups at 6 months from baseline. Secondary outcomes include differences in SAQ-summary score and additional health-status and quality of life questionnaires at 12 and 24 months from baseline. CLINICAL TRIAL REGISTRATION:International Clinical Trials Registry Platform identifier NL-OMON20739.

Background A coronary function test (CFT) is the recommended diagnostic test to identify coronary vasomotor dysfunction as a cause of symptoms in patients with angina and nonobstructive coronary arteries (ANOCA). Acetylcholine is the commonly used pharmacological agent for spasm provocation. We aimed to investigate an association between severity of symptoms and provocative acetylcholine dose. Methods and Results We included ANOCA patients undergoing clinically indicated CFT from the Netherlands Registry of Invasive Coronary Vasomotor Function Testing: NL‐CFT. Patients with epicardial spasm (n=251) were divided according to acetylcholine spasm triggering dose: low (2–20 mcg, EpiLOW), middle (100 mcg, EpiMIDDLE) or high (200 mcg, EpiHIGH). Patients with microvascular spasm (n=157) were analyzed irrespective of triggering dose. The patient groups were compared to each other and to a control group with negative CFT results (n=101). We assessed mean Seattle Angina Questionnaire angina frequency and summary scores at baseline and follow‐up and the proportion of patients improving or deteriorating. An inverse relationship between provocation dosage and angina frequency at baseline was found in epicardial spasm: the lower the triggering dose, the more frequently patients experienced angina (EpiLOW 48±20, EpiMIDDLE 53±21, EpiHIGH 57±19, microvascular spasm 61±21, controls 64±21, overall P =0.003). A trend was seen toward most patients improving in the high triggering dose group, and most patients deteriorating in the low triggering dose group. Conclusions A significant dose‐dependent relationship between spasm provocation and anginal complaints exists. Acetylcholine provocation dose could be incorporated as a risk stratification factor or surrogate outcome in future clinical trials. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06083155.

Cardiovascular disease in women has historically been underrepresented in research. In recent years, several funding bodies, including the Dutch Heart Foundation, have launched numerous research initiatives and consortia in the Netherlands to address knowledge gaps in women. This article provides an overview of the current landscape of cardiovascular disease in women and emphasizes the critical need for continued investment in this field. One area with urgent knowledge gaps is the early detection, diagnosis, therapy, and prognosis of Angina with Non-Obstructive Coronary Arteries (ANOCA) in women with persistent signs and symptoms of ischemia. In the Netherlands, in recent years, we have established a robust clinical infrastructure and a translational framework that enables us to address these challenges. Additionally, we have performed implementation studies to fast-track knowledge on ANOCA in clinical practice, giving us a unique opportunity to transform clinical care for women with signs and symptoms of ischemia. We advocate for a broad perspective that incorporates characteristics such as ethnicity, socio-economic background, and female-specific risk factors. Our goal is to provide solid evidence to ensure the best possible care for all women suffering from persistent signs and symptoms of ischemia.

Stress perfusion cardiac magnetic resonance (CMR) effectively detects myocardial ischemia. In angina with non-obstructive coronary arteries (ANOCA), visually assessed first-pass perfusion often appears normal. Automated quantitative perfusion (QP) might benefit ANOCA diagnosis, offering absolute quantification of myocardial blood flow (MBF) and myocardial perfusion reserve (MPR). We aimed to evaluate the efficacy of QP in detecting ANOCA. This study compared fully automated QP CMR in ANOCA patients with age- and sex-matched healthy controls. Participants underwent adenosine stress perfusion CMR, including visual assessment and quantification of MBF and MPR. ANOCA patients underwent coronary function testing to identify vasospasm and/or coronary microvascular dysfunction. Twenty-four ANOCA patients (83