Effect of empagliflozin on coronary microvascular function in patients with type 2 diabetes mellitus-A randomized, placebo-controlled cross-over study.

PURPOSE: Results from large scale cardiovascular outcome trials in patients with type 2 diabetes mellitus (DM2) have found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular death and hospitalization for heart failure, but the mechanisms behind the beneficial cardiovascular effects are not fully understood. We tested the hypothesis that the SGLT2i, empagliflozin, improves non-endothelial dependent coronary microvascular function, thereby leading to better cardiac function. METHODS: Patients with DM2 followed at the endocrinology outpatient clinic at Bispebjerg University Hospital were included in a double blinded, placebo-controlled cross-over study. Participants were allocated equally to each treatment sequence using simple randomization and treated with empagliflozin 25 mg and placebo for 12 weeks, interrupted by 2 weeks wash-out period. The primary outcome was coronary microvascular function, assessed as coronary flow velocity reserve (CFVR) and measured with transthoracic doppler echocardiography. Echocardiographic parameters of cardiac function were measured, and blood samples were analyzed for a broad panel of cardiovascular biomarkers. RESULTS: Thirteen patients were randomized to each sequence and 10 and 9 completed the study according to protocol, respectively, and were included in the analysis of outcome parameters. We found no improvement in CFVR (change in the empagliflozin period was -0.16 (SD 0.58)). There were no effects on cardiac systolic function or indicators of cardiac filling pressure. Well-known effects of empagliflozin were obtained, such as weight loss and reduction in Hba1c level. Creatinine level increased but remained within normal range. We observed a clear trend of reduction in cardiovascular biomarkers after empagliflozin treatment and increased levels after the placebo period. No serious adverse reactions were reported. CONCLUSIONS: Despite effect on weight-loss, Hba1c and biomarkers, treatment with empagliflozin for 12 weeks did not improve CFVR in patients with DM2.

Proteoglycan Remodeling Is Accelerated in Females with Angina Pectoris and Diffuse Myocardial Fibrosis: the iPOWER Study.

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<0.001 and r2 = 0.26, p = 0.015). Turnover of biglycan and versican was increased in angina females compared with controls and associated with extracellular volume, supporting a link between angina with no obstructive CAD and fibrotic remodeling.

Impaired coronary flow velocity reserve is associated with cardiovascular risk factors but not with angina symptoms.

OBJECTIVES: Coronary microvascular dysfunction (CMD) is considered to cause angina pectoris in a large proportion of women with no obstructive coronary artery disease (CAD). However, data supporting a relation between angina pectoris and CMD are limited. We compared CMD in women with angina with asymptomatic women and evaluated the relation between presence of CMD, angina characteristics, cardiovascular risk factors and results of stress testing. METHODS: In a cross-sectional study, we included 1684 women with angina and <50% coronary artery stenosis on invasive angiography. Asymptomatic women from the community-based Copenhagen City Heart Study served as reference group (n=102). Coronary microvascular function was determined by coronary flow velocity reserve (CFVR) assessed by transthoracic Doppler stress echocardiography. CFVR < 2 was defined as CMD. Symptoms were obtained from standardised angina questionnaires and results of stress testing from health records. RESULTS: Median CFVR was 2.33 (IQR 2.00-2.75) in symptomatic women versus 2.60 (2.19-2.95) in asymptomatic (p=0.007). CFVR <2 was found in 25% of symptomatic and in 19% of asymptomatic women. Symptomatic women had a greater risk factor burden. After adjusting for age, hypertension, diabetes, smoking and heart rate the difference in CFVR between groups disappeared (p=0.213). We found no associations between CFVR and angina characteristics, symptom burden or results from stress testing. CONCLUSIONS: Impaired CFVR is more prevalent in symptomatic than in asymptomatic women and related to the cardiovascular risk factors hypertension, diabetes, smoking and increased heart rate. Neither a positive bicycle test, single photon emission CT stress test nor chest pain characteristics identify women with impaired CFVR among women with angina and no obstructive CAD. Results may question the concept of microvascular angina as currently defined.

Comprehensive treatment of microvascular angina in overweight women - a randomized controlled pilot trial.

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<0.01)) but had no effect on CFVR (p = 0.468). Mean (CI) weight loss was 9.6 (7.80;11.48) kg, (p<0.0001). There was a significant mean (CI) decrease in depression symptoms = 1.16 (0.22;2.12), triglycerides = 0.52 (0.25;0.78) mmol/L, total cholesterol = 0.55 (0.12;0.98) mmol/L, and HbA1c in diabetics = 27.1 (1.60;52.6) mmol/mol but no effect on other secondary outcomes. 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.

Women with coronary microvascular dysfunction and no obstructive coronary artery disease have reduced exercise capacity.

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 ±â€¯standard deviation) 61 ±â€¯10 and 58 ±â€¯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 < 0.001) and blunted heart rate recovery. 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.

Pro-inflammatory biomarkers in women with non-obstructive angina pectoris and coronary microvascular 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 (<50% stenosis on invasive coronary angiography), CMD was assessed by transthoracic Doppler echocardiography measuring coronary flow velocity reserve (CFVR). Blood samples were analyzed with a CVD proteomic panel encompassing 92 biomarkers. The relation between biomarkers and CFVR was evaluated by regression analysis, and possible interrelations between significant biomarkers were investigated by principal component analysis (PCA). RESULTS: Median age (SD) was 64 years (9.8), median CFVR (IQR) was 2.3 (1.9-2.7), and 28% of patients had CFVR < 2.0. Eighteen biomarkers were significantly correlated with CFVR. In PCA, 8 of the biomarkers significantly related to CFVR showed high loadings on principal component 1 (PC1). The component scores of PC1 were significantly related to CFVR (p = 0.002). The majority of the 8 interrelated PC1 biomarkers were related to the pro-inflammatory TNF-α - IL-6 - CRP pathway. CONCLUSION: Eighteen protein biomarkers were significantly associated with CMD. Eight biomarkers were interrelated in PCA, and share connection with pro-inflammatory pathways, highlighting a possible important role of inflammation in CMD.

The effect of DPP-4-protected GLP-1 (7-36) on coronary microvascular function in obese adults.

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 ±â€¯1.25 during GLP-1 infusion and 3.85 ±â€¯1.32 during saline infusion, endothelial function was 16.3 ±â€¯15.5 % during GLP-1 infusion and 7.85 ±â€¯7.76 % during saline infusion. When adjusting for baseline values no significant differences in CFVR (ΔCFVR 0.38 ±â€¯0.92 vs. ΔCFVR 0.71 ±â€¯1.03, p = 0.43) and no difference in peripheral endothelial function (ΔFMD 7.34 ±â€¯11.5 % vs. ΔFMD -1.25 ±â€¯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.

Protein biomarkers and coronary microvascular dilatation assessed by rubidium-82 PET in women with angina pectoris and no obstructive coronary artery disease.

BACKGROUND AND AIMS: While a plethora of biomarkers have been shown to be associated with coronary artery disease, studies assessing biomarkers in coronary microvascular dysfunction (CMD) are few. We investigated associations between cardiovascular protein biomarkers and non-endothelium dependent CMD assessed by positron emission tomography (PET). METHODS: In 97 women with angina pectoris and no significant obstructive coronary artery disease (<50% stenosis on invasive coronary angiography), CMD was defined as myocardial blood flow reserve (MBFR) < 2.5 by rubidium-82 PET. Blood samples were analyzed with a cardiovascular disease proteomic panel encompassing 92 biomarkers. The relation between MBFR and biomarkers was evaluated with age-adjusted regression analysis. RESULTS: Median age was 62 years (range 31-79), median MBFR was 2.7 (range 1.2-4.7) and 32% had non-endothelium dependent CMD (MBFR<2.5). Four biomarkers were significantly correlated with MBFR: Galectin-4 (Gal4, p = 0.008), growth differentiation factor 15 (GDF15, p = 0.026), tissue-type plasminogen activator (tPA, p = 0.030) and von Willebrand factor (vWF, p = 0.018), while 12 biomarkers showed a trend for correlation (0.05 ≤ p < 0.15). Of the 16 identified biomarkers, 10 are involved in pro-inflammatory pathways. CONCLUSIONS: In a panel of 92 cardiovascular protein biomarkers, 4 were significantly associated with non-endothelium dependent CMD in women: Gal4, GDF15, tPA and vWF, suggesting that inflammatory status and coagulation changes are associated with impaired microvascular dilatation. Further confirmatory studies are needed to corroborate these findings.

Anxiety and depression are more prevalent in patients with graves' disease than in patients with nodular goitre.

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.

Association between smoking and the risk of heavy drinking among young women: a prospective study.

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.