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BackgroundMore than half of women with symptoms suggestive of myocardial ischaemia have no obstructive coronary artery disease (CAD), yet they face a higher risk of cardiovascular mortality and morbidity. Both vital exhaustion (VE) and depression have been linked to adverse cardiovascular prognosis in patients with CAD. We aimed to assess whether symptomatic women with no obstructive CAD are more vitally exhausted compared with asymptomatic women. Furthermore, we investigated the overlap between the constructs of VE and depression.MethodsPrevalence and burden of VE was assessed in symptomatic women with no obstructive CAD (n=1.266) and asymptomatic women (n=2.390). Among symptomatic women, we also assessed chest pain characteristics and symptoms of Hospital Anxiety and Depression Questionnaire.FindingsMedian (IQR) VE score was 4 (1-9) and 2 (0–5) in symptomatic and asymptomatic women, respectively (age adjusted, pConclusionsWomen with chest pain and no obstructive CAD are more vitally exhausted compared with asymptomatic women. PCCA showed that VE is distinct from depression in symptomatic women.Clinical implicationsMental health screening focusing on depressive symptomatology in women with chest pain presenting with symptoms of mental and physical exhaustion may overlook VE in these patients.

Background Both coronary microvascular dysfunction (CMD) and reduced exercise capacity are associated with adverse cardiovascular prognosis. The association between CMD and cardiopulmonary exercise testing (CPET) derived exercise capacity in symptomatic individuals without obstructive coronary artery disease (CAD) is not clear. We investigated whether exercise capacity was reduced in women with angina, CMD and no obstructive CAD compared with sex-matched controls. Furthermore, we assessed the association between CMD and other CPET-derived variables. Methods All participants underwent transthoracic Doppler echocardiography of the left anterior descending artery with dipyridamole-induced vasodilation and CPET using ergometer cycle with an incremental test protocol. Results We included 99 women with angina and no obstructive CAD (patients) and 27 asymptomatic women (controls), age (mean ± standard deviation) 61 ± 10 and 58 ± 10 years, respectively. Patients had a higher burden of risk factors compared with controls, while the weekly physical activity level was comparable between the groups (p = 0.72). CMD was present in 27 (27%) patients and 5 (19%) controls. Peak VO2 was significantly reduced in patients with CMD compared with controls with normal coronary microvascular function ((median (IQR) 17.3 (15.5–21.3) vs. 27.3 (21.6–30.8) ml/kg/min; age-adjusted p = 0.001), independent of cardiovascular risk factors (p = 0.041). Presence of CMD in symptomatic women was also associated with diminished heart rate reserve (p Conclusions Women with angina, CMD and no obstructive CAD have markedly reduced exercise capacity compared with sex-matched controls. Moreover, combination of angina and CMD is associated with impaired heart rate response and heart rate recovery.

Background Coronary microvascular dysfunction (CMD) is associated with adverse cardiovascular outcomes and CMD is a hallmark of type 2 diabetes. Liraglutide improves cardiovascular prognosis through partly unknown mechanisms. We hypothesized that treatment with liraglutide improves CMD and symptoms through weight loss, in non-diabetic overweight patients with angina and no obstructive coronary artery disease (CAD). Methods We included 33 non-diabetic overweight women (BMI > 25) with CMD (Coronary flow velocity reserve (CFVR) ≤2.5), angina symptoms and no obstructive CAD, in an open-label proof-of-concept study. The protocol included a control period of 5 weeks followed by an intervention period with liraglutide aiming at 3 mg daily for 12 weeks. Participants were investigated before and after the control period and again 1–2 weeks after last liraglutide dose. Primary outcomes were change in CFVR and change in angina symptoms measured by the Seattle Angina Questionnaire (SAQ) in the intervention period compared with the control period. ( clinicaltrials.gov , NCT02602600, and ethically approved). Results Twenty-nine participants completed the study. Liraglutide treatment led to a significant weight loss (mean 6.03 kg (95%CI: 5.22;6.84)) and decrease in systolic blood pressure (mean 10.95 mm Hg (95%CI: 4.60;17.30)). Baseline median CFVR was 2.30 (IQR 1.91;2.51) and remained unchanged after liraglutide treatment (mean change 0.07 (95%CI: −0.07;0.21)). There were no effects on symptoms measured by SAQ or parameters of left ventricular systolic as well as diastolic function. Conclusions Treatment with liraglutide led to significant weight loss and lowering of blood pressure with no concomitant symptoms alleviation during treatment and no improvement in coronary microvascular function.

Aims Many patients with angina, especially women, do not have obstructive coronary artery disease (CAD) yet have impaired prognosis. We investigated whether routine assessment of coronary microvascular dysfunction (CMD) is feasible and predicts adverse outcome in women with angina and no obstructive CAD. Methods and results After screening 7253, we included 1853 women with angina and no obstructive CAD on angiogram who were free of previous CAD, heart failure, or valvular heart disease in the prospective iPOWER (Improving Diagnosis and Treatment of Women with Angina Pectoris and Microvascular Disease) study. CMD was assessed by Doppler echocardiography in the left anterior descending artery as coronary flow velocity reserve (CFVR). Patients were followed for a composite outcome of cardiovascular death, myocardial infarction (MI), heart failure, stroke, and coronary revascularization. CFVR was obtained in 1681 patients (91%) and the median CFVR was 2.33 (quartiles 1–3: 2.00–2.74). During a median follow-up of 4.5 years, 96 events occurred. In univariate Cox regression, CFVR was associated with the composite outcome {hazard ratio (HR) 1.07 [95% confidence interval (CI) 1.03–1.11] per 0.1 unit decrease in CFVR; P Conclusion Assessment of CFVR by echocardiography is feasible and predictive of adverse outcome in women with angina and no obstructive CAD. Results support a more aggressive preventive management of these patients and underline the need for trials targeting CMD.

Angina and no obstructive coronary artery disease (CAD) have an unfavorable prognosis, possibly due to diffuse myocardial fibrosis (DMF). In DMF the proteoglycans biglycan and versican are actively remodeled by matrix metalloproteinase. We investigated biglycan and versican in females with angina and possible DMF assessed by cardiac magnetic resonance (CMR). Seventy-one females with angina and no obstructive CAD were included. Asymptomatic females served as controls. Versican and biglycan were measured and CMR was performed measuring extracellular volume. Biglycan and versican levels were higher in symptomatic females compared with controls; 31.4 ng/mL vs. 16.4 ng/mL (p < 0.001) and 2.1 ng/mL vs. 1.8 ng/mL (p < 0.001) and moderately correlated to extracellular volume (r2 = 0.38, p

Background Women with angina and no obstructive coronary artery disease (CAD) have an unfavourable prognosis, possibly due to coronary microvascular disease and diffuse myocardial fibrosis (DMF). In DMF myocardial extracellular matrix (ECM) proteins are actively remodeled by matrix metalloproteinase (MMP). Purpose We investigated MMP-mediated degradation of the protegoglycans biglycan and versican in women with angina pectoris and possible DMF assessed by cardiac magnetic resonance T1 mapping. Methods Seventy-one women with angina pectoris and no obstructive CAD were included. Asymptomatic age-matched women served as controls (n=32). Versican and biglycan were measured in serum by specific competitive enzyme-linked immunosorbent assays. T1 mapping was performed by cardiac magnetic resonance with gadolinium measuring T1 and extracellular volume (ECV). Results Both biglycan and versican levels were higher in symptomatic women compared with controls; 31.4 ng/mL vs. 16.4 ng/mL (p Conclusion Turnover of biglycan and versican was increased in symptomatic compared to asymptomatic women and associated to ECV, supporting a link between angina with no obstructive CAD and fibrotic cardiac remodeling. The examined biomarkers may prove to be suitable for monitoring active ECM remodeling. Figure 1. Levels of BGM and VCANM Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This work was supported by The Danish Heart Foundation, the Danish Research Fund (Den Danske Forskningsfond) and by University of Copenhagen.

Aims Coronary microvascular dysfunction (CMD) carries a poor cardiovascular prognosis and may explain angina in women without obstructive coronary artery disease (CAD). Currently, no evidence-based treatment for CMD exists. We investigated whether reducing cardiovascular risk factors improves symptoms and microvascular function in women with non-endothelial dependent CMD and no obstructive CAD. Methods We randomized 62 women aged 40–75, with body mass index (BMI) >25 kg/m2, angina ≥monthly, and coronary flow velocity reserve (CFVR) ≤2.5 to a 24-week intervention comprising low energy diet, exercise training, and optimized treatment of hypertension, dyslipidemia and diabetes or to control. Patients were assessed before randomization and after 24 weeks. Primary outcomes were CFVR assessed by transthoracic Doppler stress-echocardiography and angina burden by Seattle Angina Questionnaire (SAQ). Secondary outcomes were exercise capacity, body composition, glycemic control, myocardial function, and anxiety and depression symptoms. Results Fifty-six participants (90%) completed the study. Median (IQR) age was 65.2 (57.1;70.7) years, BMI was 30.1 (28.4;32.7) kg/m2. The intervention resulted in relevant improvement in angina symptoms (9-21-point increase on SAQ-scales (all p Conclusion A major weight loss and intensified risk factor control resulted in significantly improved angina burden but no improvement of coronary microvascular function among women with microvascular angina.

Reproductive risk factors such as preeclampsia and recurrent miscarriages have been associated with adverse cardiovascular (CV) events. Underlying coronary microvascular dysfunction (CMD) may be a common denominator.We investigated whether a history of reproductive risk factors was associated with CMD in women with angina pectoris and no obstructive coronary artery disease (CAD).Participants from the iPOWER study, including women with angina pectoris and no obstructive CAD (50% stenosis), were invited to complete an electronic survey regarding reproductive risk factors: recurrent miscarriages, gestational diabetes, preeclampsia, rhesus immunity, polycystic ovary syndrome and menopausal status as well as migraine and Raynaud phenomenon. CMD was assessed by transthoracic Doppler echocardiography with measurement of coronary flow velocity reserve (CFVR) during high-dose dipyridamole infusion, and analyzed in three categories with cut-off points at 2.0 and 2.5. Associations between CFVR and a history of reproductive risk factors were examined by age-adjusted trend test.The questionnaire was completed by 613 women (73% of those invited), of whom 550 had a successful CFVR measurement. There was no significant difference in baseline characteristics between participants and non-participants. Median (interquartile range (IQR)) age was 62.8 (54.8; 68.7) years, median (IQR) BMI 26.2 (23.2; 29.8) kg/mThe lack of association between coronary microvascular function and a history of reproductive risk factors, migraine and Raynaud's phenomenon suggests that a common vascular pathophysiological mechanism underlying these conditions is unlikely.

Objective: Glucagon-like-peptide-1 (GLP-1) receptor analogues have been shown to reduce cardiovascular events in patients with type 2 diabetes. However, the mechanism behind is still unknown. The aim of the study was to investigate the effect of intact GLP-1 (7–36) on coronary microcirculation in overweight adults. Design and methods: A double-blinded randomized cross-over study was performed, with 12 overweight participants. Effects of intact GLP-1 (7-36) infusion were compared with a saline infusion on separate days. A DPP-4 inhibitor was administered to block degradation of intact GLP-1 (7–36) to the GLP-1 metabolite (9–36). Coronary microcirculation was assessed by Doppler coronary flow velocity reserve (CFVR) before and after 2 h of infusion. Peripheral endothelial function was assessed by flow mediated dilation (FMD) before and after one hour of infusion. Results: CFVR was 3.77 ± 1.25 during GLP-1 infusion and 3.85 ± 1.32 during saline infusion, endothelial function was 16.3 ± 15.5 % during GLP-1 infusion and 7.85 ± 7.76 % during saline infusion. When adjusting for baseline values no significant differences in CFVR (ΔCFVR 0.38 ± 0.92 vs. ΔCFVR 0.71 ± 1.03, p = 0.43) and no difference in peripheral endothelial function (ΔFMD 7.34 ± 11.5 % vs. ΔFMD –1.25 ± 9.23%, p = 0.14) was found. Conclusions: We found no effect of intact GLP-1 (7–36), protected from DPP4 mediated degradation on coronary microcirculation in overweight adults. Keywords: Coronary microcirculation, Coronary flow velocity reserve, Glucagon-like peptide-1 (7–36), GLP-1, flow mediated dilation, Endothelial function

PurposeSystemic inflammation and coronary microvascular dysfunction (CMD) may be causal drivers of heart failure with preserved ejection fraction (HFpEF). We tested the hypothesis that subclinical inflammation is associated with non-endothelial dependent CMD and diastolic dysfunction.MethodsIn a cross-sectional study of 336 women with angina but no flow limiting coronary artery stenosis (180 with diabetes) and 95 asymptomatic controls, blood samples were analysed for 90 biomarkers of which 34 were part of inflammatory pathways. CMD was assessed as coronary flow velocity reserve (CFVR) by transthoracic Doppler echocardiography and defined as CFVRResultsCMD was found in 59% of participants whereas only 4% fulfilled strict criteria for diastolic dysfunction. Thirty-five biomarkers, 17 of them inflammatory, were negatively correlated with CFVR and 25, 15 inflammatory, were positively correlated with E/e'. A total of 13 biomarkers, 9 inflammatory, were associated with both CFVR and E/e'. CFVR and E/e' were only correlated in the subgroup of patients with CMD and signs of increased filling pressure (E/e'>10) (p = 0.012).ConclusionThis is the first study to link a large number of mainly inflammatory biomarkers to both CMD and E/e', thus confirming a role of inflammation in both conditions. However, despite a high prevalence of CMD, few patients had diastolic dysfunction and the data do not support a major pathophysiologic role of non-endothelial dependent CMD in diastolic dysfunction.

Background: Studies that evaluate larger numbers of protein biomarkers in patients with coronary microvascular dysfunction (CMD) have not previously been performed, and very little is known concerning the pathogenetic mechanisms leading to CMD.Our objective was to analyze associations between a broad cardiovascular disease (CVD) protein biomarker assay and CMD, and further explore internal biomarker relations in order to identify possible targets for future treatment interventions. Methods: In 174 women with angina pectoris and no significant obstructive coronary artery disease (

Udgivelsesdato: null-null AIM: To address the association between smoking habits and the risk of later heavy drinking among young women. METHODS: Repeated assessments of alcohol and smoking habits were obtained in 1991-93 and 1999-2000 in a Danish representative cohort in Copenhagen. A total of 6369 non- to moderate-drinking Danish women, aged 20-29 years at baseline, attended a follow-up examination and were included in the study. The risk of becoming a heavy drinker (more than 14 drinks per week) 8 years after enrolment was analyzed by means of logistic regression. RESULTS: A total of 177 women became heavy drinkers during follow-up. Daily smoking at baseline was associated with an increased risk of becoming a heavy drinker 8 years later. Relative to nonsmokers, the adjusted odds ratios (OR) for becoming a heavy drinker associated with smoking 1-14, 15-24, or more than 24 cigarettes per day were 1.6 (95% confidence intervals (CI) 1.1-2.4), 1.7 (CI 1.1-2.6), and 2.3 (CI 0.9-5.9), respectively. Age at sexual debut modified the effect of smoking, and women with a debut before the age of 15 years had an adjusted OR of 2.9 (CI 1.1-3.9) compared to never-smokers while there seemed to be no effect among women with a sexual debut after the age of 18. In addition, relative to nondrinkers, all of the moderate (1-5 units per week), medium (6-10 units), and large (10-14 units) alcohol consumption at baseline were associated independently with becoming a heavy drinker 8 years later. CONCLUSIONS: This study suggests that smoking is an important predictor of later heavy drinking among young women and that this relatively elevated risk is most pronounced among women with an early sexual debut.

BACKGROUND AND OBJECTIVE: Graves' disease has been associated with an increased psychiatric morbidity. It is unclarified whether this relates to Graves' disease or chronic disease per se. The aim of our study was to estimate the prevalence of anxiety and depression symptoms in patients with Graves' disease compared to patients with another chronic thyroid disease, nodular goitre, and to investigate determinants of anxiety and depression in Graves' disease.METHODS: 157 cross-sectionally sampled patients with Graves' disease, 17 newly diagnosed, 140 treated, and 251 controls with nodular goitre completed the Hospital Anxiety and Depression Scale (HADS). The differences in the mean HADS scores between the groups were analysed using multiple linear regression, controlling for socio-demographic variables. HADS scores were also analysed dichotomized: a score >10 indicating probable 'anxiety'/probable 'depression'. Determinants of anxiety and depression symptoms in Graves' disease were examined using multiple linear regression.RESULTS: In Graves' disease levels of anxiety (p = 0.008) and depression (p = 0.014) were significantly higher than in controls. The prevalence of depression was 10% in Graves' disease versus 4% in nodular goitre (p = 0.038), anxiety was 18 versus 13% (p = 0.131). Symptoms of anxiety (p = 0.04) and depression (p = 0.01) increased with comorbidity. Anxiety symptoms increased with duration of Graves' disease (p = 0.04). Neither thyroid function nor autoantibody levels were associated with anxiety and depression symptoms.CONCLUSIONS: Anxiety and depression symptoms were more severe in Graves' disease than in nodular goitre. Symptoms were positively correlated to comorbidity and duration of Graves' disease but neither to thyroid function nor thyroid autoimmunity.