N. Charlotte Onland-Moret

Background and Aims: Comprehensive evaluation by invasive coronary function test (CFT) of patients with angina and non-obstructive coronary artery disease is recommended in the current guidelines. The prognosis of patients with CFT-proven coronary vasomotor dysfunction (CVDys) is less well-known. Methods: Patients that provided consent for the previously published NL-CFT registry who underwent clinically indicated invasive CFT between 1 February 2019 and 1 June 2024 were included. Patients with CVDys, defined as an abnormal spasm provocation test and/or microvascular functional assessment, were compared to patients with normal CFT. The primary outcome of major adverse cardiovascular events and emergency room visits for angina (MACE-EA) was defined as a composite of all-cause death, acute coronary syndrome, stroke/transient ischaemic attack, revascularization, repeat angiography without intervention, heart failure hospitalizations, and unplanned hospitalizations or emergency room visits due to angina. Results: In total, 1355 patients were included. In 79.8%, CFT was abnormal, and vasospasm was the most prevalent endotype. In 1252 patients, follow-up of clinical events was complete. During a mean follow-up of 33 ± 13 months, CVDys patients had almost double the number of primary outcome events compared with patients with a normal CFT (31.2% vs 16.8%, P < .001), driven by emergency care visits for angina. Secondary clinical endpoints including death, myocardial infarction, stroke, or revascularization were low and comparable between the groups. Conclusions: The long-term risk of MACE-EA is doubled in ANOCA patients with CFT-confirmed CVDys compared with normal CFT results. Events are dominated by emergency room visits due to angina, illustrating the high disease burden of CVDys. Their (angina-related) health status is significantly worse at follow-up.

Background: Endometriosis has been associated with a higher risk of cardiovascular disease (CVD), but the underlying mechanisms remain incompletely understood. Methods: Using UK Biobank data, we assessed the relationship between endometriosis and CVD (defined as a composite of fatal and non‐fatal coronary heart disease, peripheral artery disease, and stroke), cardiovascular mortality, and all‐cause mortality, applying Cox regression analysis while adjusting for conventional and emerging, lifestyle and demographic, and female‐specific CVD risk factors. Furthermore, we performed subgroup analysis across age and female‐specific factors, and mediation analysis to study the role of hysterectomy and oophorectomy. Results: We included 264 740 women without CVD at baseline (median age 57 [25th–75th percentile 50–63] years; 8194 with endometriosis) from the UK Biobank. During 3 484 788 person‐years of follow‐up, 22 283 women developed CVD. Endometriosis was associated with an 18% higher risk of CVD (hazard ratio 1.18 [95% CI 1.10–1.28]), mainly driven by coronary heart disease (1.24 [1.12–1.37]). Conversely, endometriosis was related to a 12% lower risk of all‐cause mortality (0.88 [0.80–0.98]). The association with cardiovascular mortality was not significant (0.85 [0.63–1.13]). Mediation analysis suggested that hysterectomy may partially mediate the association between endometriosis and CVD. Subgroup analyses did not yield significant differences. Conclusions: Endometriosis is associated with a higher risk of CVD, especially coronary heart disease. Mediation analysis suggests that hysterectomy partly explains this association. Whether hysterectomy may proxy endometriosis severity instead of being a true mediator remains to be elucidated. These findings highlight the need for studies that unravel the causal mechanisms linking endometriosis, its treatments, and cardiovascular outcomes.

Background: Diagnosing heart failure with preserved ejection fraction (HFpEF) can be challenging because natriuretic peptide (NP) plasma levels and diastolic function parameters during rest echocardiography may be normal or marginally abnormal in patients displaying exercise-induced symptoms suggestive of HF. In these patients exercise echocardiography is recommended. We wanted to assess whether directly measured NP levels post-exercise had added diagnostic value beyond rest plasma N-terminal pro-brain NP (NT-proBNP) levels for diagnosing HFpEF. Methods: Participants with left ventricular diastolic dysfunction (LVDD), who could not be classified as HFpEF by a panel of experts more than 4 years ago, were prospectively enrolled in the HELPFulUP observational study from August 2021 to October 2022. All participants in the HELPFulUP study underwent clinical assessment, rest and exercise-echocardiography and measurements of plasma NT-proBNP before and directly after exercise. An expert panel, blinded to exercise NT-proBNP results, but with knowledge of signs, symptoms and all other diagnostic parameters including baseline values of NT-proBNP adjudicated HFpEF status. We calculated the area under the receiver operating characteristic curve (area under the curve (AUC)) for HFpEF for rest and post-exercise NT-proBNP levels and the delta NT-proBNP. Results: Of the 112 LVDD participants (59 women), 11 were diagnosed with HFpEF by the expert panel based on the additional information retrieved from exercise echocardiography, and 101 remained classified as LVDD. Rest (AUC=0.78 (95% CI 0.66 to 0.90) and exercise values of NT-proBNP (AUC=0.77 (95% CI 0.65 to 0.90) had similar discriminatory value. The delta NT-proBNP AUC was 0.53 (95% CI 0.31 to 0.75). Conclusions: In this pilot study, the diagnostic performance of the change with exercise in NP levels to detect incident HFpEF, beyond measurements in rest, did not point to a strong diagnostic value.

Assessment of biological aging using proteomic clocks may enhance risk prediction and elucidate the molecular links between aging and chronic diseases. Here, among 17,473 participants of the European Prospective Investigation into Cancer and Nutrition, we examined associations of plasma SomaScan-based proteomic clocks, including organ-specific clocks, with risk factors, 24 incident chronic diseases and all-cause mortality, over up to 28 years of follow-up. Replication was conducted in the Whitehall II study. We show that the global age gap, an age acceleration score combining proteomic clocks, was associated with smoking, alcohol consumption, physical inactivity and higher risk of mortality, cardiovascular diseases, dementia and cancers of the liver, upper aero-digestive tract, lung and kidney. Lung, kidney and stomach cancers were more strongly associated with related organ-specific age gaps. Predictive performance of proteomic clocks for mortality was comparable to that of classical lifestyle risk factors. In summary, proteomic clocks appear promising biomarkers of generalized age-related disease risk.

Most physical activity research focuses on general populations, and its cancer-preventive benefits in adults with cardiometabolic diseases remain poorly understood. This study investigated associations between non-occupational physical activity and cancer risk in adults with and without cardiometabolic diseases (cardiovascular disease and/or type 2 diabetes). We conducted a meta-analysis of individual participant data of 598,890 men and women, aged 35-70 years at recruitment, across six European countries from the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank. Participants with cancer at baseline were excluded. Physical activity was assessed at baseline using self-reported validated questionnaires. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between non-occupational physical activity and the risk of physical activity-related cancers (a composite of 15 cancers), with a multiplicative interaction between non-occupational physical activity and time-varying cardiometabolic disease status. We show that after a median follow-up of 11 years, 37,182 participants developed a first primary physical activity-related cancer (EPIC and UK Biobank combined). In the meta-analysis of both cohorts, a 1 standard deviation increment of non-occupational physical activity is associated with a lower risk of physical activity-related cancer, with HRs of 0.96 (95% CI: 0.93, 0.98) and 0.93 (95% CI: 0.91, 0.96) in adults without and in those with a cardiometabolic disease, respectively (all p-interaction ≥ 0.17). The findings of this study suggest that higher non-occupational physical activity is equally beneficial for cancer prevention in adults with and without cardiometabolic diseases.

Background: Moderate-to-vigorous physical activity (MVPA) is inversely associated with risks of cancer, cardiovascular diseases (CVD), type 2 diabetes (T2D), and their co-occurrence, defined as multimorbidity; however, the underlying biological pathways remain unclear. Methods: In 33,806 UK Biobank participants with 2911 measured blood proteins, a proteomic signature of MVPA was derived with linear and LASSO regressions. Multivariable Cox models, adjusted for MVPA, estimated prospective associations with cancer, CVD, T2D, and multimorbidity. Results: We show that after multiple testing corrections, 220 proteins are retained in the MVPA signature. Proteins related to food intake, metabolism, and cell growth (e.g., LEP, MSTN) are inversely associated, while those involved in immune cell migration and musculoskeletal integrity (e.g., integrins, COMP) are positively associated with MVPA. Several proteins positively associated with MVPA are inversely associated with disease risk (e.g., integrins, CLEC4A for cancer; LPL, LEP for T2D), while proteins negatively associated with MVPA are positively associated with disease risk (e.g., CD38, TGFA for CVD). The proteomic signature score is inversely associated with cancer risk (hazard ratio per interquartile range: 0.87; 95% confidence interval: 0.78, 0.96) and T2D (0.66; 0.60, 0.72). For multimorbidity, proteins inversely related to MVPA align with expected risk patterns (e.g., GGT1, HR: 1.32; 95% CI: 1.12, 1.57), but the proteomic signature score is not associated. Conclusions: This study identifies several proteins associated with MVPA that are also associated with cancer, CVD, T2D, and the multimorbidity of these conditions. Further studies investigating the causal nature of these associations are welcome.

Background and aims: The Heavy, Hypertensive, Atrial fibrillation, Pulmonary hypertension, Elder, Filling pressure (H ₂ FPEF) score is a widely used diagnostic tool for heart failure with preserved ejection fraction (HFpEF). Angina symptoms are common in patients with HFpEF but are not included in the score. We aimed to determine whether incorporating angina into the H ₂ FPEF score improves its diagnostic performance sex-specifically, given the well-known sex differences in both HFpEF and angina presentation. Methods: We included 515 individuals from the UHFO-DM cohort with suspected HFpEF. Participants underwent standardised symptom collection, including angina using WHO questionnaires, and expert-panel adjudication of HFpEF. Following evaluation of H ₂ FPEF, we assessed the association of angina with HFpEF independent of H ₂ FPEF using logistic regression. By adding angina to H ₂ FPEF, we developed a modified algorithm and evaluated it by the area under the receiver operating characteristic curve (AUC), calibration, reclassification and decision curve analysis. All analyses were stratified by sex. We also included another 751 individuals with suspected HFpEF from a Combination cohort of UHFO-COPD (n=136), STRETCH (n=331) and TREE (n=284) for regression analysis. Results: In the UHFO-DM cohort, HFpEF prevalence was 24%. Overall H ₂ FPEF discrimination (AUC) was 0.72, with 0.69 in women and 0.74 in men. Angina was independently associated with HFpEF in women (OR 3.96, 95% CI 1.72 to 9.11, p=0.001) but not in men (1.90, 0.88 to 4.10, 0.102). Adding one point for angina in a modified H ₂ FPEF score in women improved AUC from 0.69 to 0.71 (DeLong p=0.030), increased sensitivity (0.53 to 0.60) and negative predictive value (0.80 to 0.82) and yielded a continuous net reclassification improvement of 0.449, with preserved calibration and higher net clinical benefit on decision curves. No performance gain was observed with the same modification in men. In the Combination cohort, angina was also independently associated with HFpEF only in women (women, 2.13, 1.14 to 3.97, 0.018; men, 0.85, 0.44 to 1.66, 0.638). Conclusions: In women with suspected HFpEF, the presence of angina provides diagnostic information independent of H ₂ FPEF to uncover HFpEF. A simple sex-specific modification of H ₂ FPEF, adding one point for angina in women, may slightly improve discrimination and rule-out performance in women.

Purpose Whether physical activity is associated with the risk of cancer among adults with a cardiometabolic disease is not well understood. This study investigated associations between physical activity and cancer risk in adults with and without a history of cardiometabolic diseases (cardiovascular disease and/or type 2 diabetes). Methods We conducted a meta-analysis of individual participant data of 564,622 men and women, aged 35–70 years at recruitment, across six European countries from the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank. We excluded participants from these cohorts who had cancer, cardiovascular disease, or type 2 diabetes at baseline. Data on physical activity were assessed at baseline with self-reported validated questionnaires and modelled as metabolic equivalent task hours per week (MET-h/week). We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between physical activity and the risk of physical activity-related cancers, with a multiplicative interaction between physical activity and time-varying cardiometabolic disease status. Results After a median of 11 years of follow-up, 28,345 participants developed a first primary physical activity-related cancer (EPIC and UK Biobank combined). In the meta-analysis of both cohorts, a 1 standard deviation (SD) increment of physical activity was associated with a lower risk of physical activity-related cancer, with HRs of 0.96 (95% CI: 0.95, 0.97) and 0.94 (95% CI: 0.90, 0.99) in adults without and in those with a cardiometabolic disease, respectively (p-interaction > 0.3). Conclusions The findings of this study among European adults suggest that higher physical activity is equally beneficial for cancer prevention in adults with and without underlying cardiometabolic diseases.

Aims: A history of pre-eclampsia is associated with at least a two-fold increased risk of coronary artery disease (CAD), with unclear underlying mechanisms. This study aimed to investigate coronary plaque characteristics in women with a history of pre-eclampsia compared with women from the general population. Methods and results: In this cross-sectional study, women with a history of pre-eclampsia from the Cardiovascular Riskprofile—Imaging and Gender-Specific Disorders (CREw-IMAGO) study (n = 138) were compared with a reference group of women without a self-reported history of pre-eclampsia from the Swedish Cardiopulmonary Bioimage study (SCAPIS, n = 390). All participants (age 45–55 years) underwent coronary computed tomography angiography (CCTA). Plaques were assessed quantitatively with semi-automated software for total, calcified, and non-calcified plaque volumes. Differences in plaque characteristics were analyzed using multivariable linear regression analyses. Women with a history of pre-eclampsia had a two-fold increased risk of having any coronary plaque. Among women with plaques, a history of pre-eclampsia was associated with a larger non-calcified plaque volume (beta: 0.62; 95% CI: 0.17–1.07) after adjustment for age, body mass index, education, dyslipidaemia, and a history of smoking. This was explained by larger volumes of fibrous plaque (beta: 0.71; 95% CI: 0.26–1.15) and fibrous fatty plaque (beta: 0.52; 95% CI: 0.01–1.03) and not due to a larger total plaque volume. Conclusion: Women with a history of pre-eclampsia have coronary plaques with larger non-calcified plaque volume compared with unaffected women, driven by larger fibrous and fibrous fatty plaque volumes, independent of total plaque volume.

Background and Aims: The H ₂ FPEF score is a widely used prediction tool used during the diagnostic work-up of heart failure with preserved ejection fraction (HFpEF). However, having angina symptoms is not included in the score, despite being common in patients with HFpEF. We hypothesize that incorporating angina in the H ₂ FPEF score may improve its performance. Given the known sex differences in HFpEF, sex-specific analyses are warranted. Methods: We included 1,266 individuals suspected HFpEF, with 515 from the UHFO-DM cohort and 751 from a combination cohort of STRETCH, TREE and UHFO-COPD. Participants underwent standardized symptom collection, including angina, using WHO questionnaires and expert-panel adjudication of HFpEF. Following evaluation of H ₂ FPEF, we assessed the association of angina with HFpEF independent of H ₂ FPEF using logistic regression. By adding angina to H ₂ FPEF, we developed a modified algorithm and evaluated it by AUC, calibration, reclassification, and decision curve analysis. All analyses were stratified by sex. Results: In the UHFO-DM cohort, HFpEF prevalence was 24%. Overall H ₂ FPEF discrimination (AUC) was 0.72, with 0.69 in women and 0.74 in men. Angina was independently associated with HFpEF in women (OR 3.96, 95% CI 1.72–9.11, P=0.001) but not in men (1.90, 0.88–4.10, 0.102). This was also found in the combination cohort (women: 2.13, 1.14–3.97, 0.018; men: 0.85, 0.44–1.66, 0.638). In the UHFO-DM cohort, adding one point for angina in a modified H ₂ FPEF score in women improved AUC from 0.69 to 0.71 (DeLong P=0.030), increased sensitivity (0.53 to 0.60) and negative predictive value (0.80 to 0.82), and yielded a continuous net reclassification improvement of 0.449, with preserved calibration and higher net clinical benefit on decision curves. No performance gain was observed with the same modification in men. Conclusions: In women with suspected HFpEF, presence of angina provides diagnostic information independent of H ₂ FPEF to uncover HFpEF. A simple sex-specific modification of H ₂ FPEF, adding one point for angina in women, may slightly improve discrimination and rule-out performance in women. GRAPHICAL