Marie Mide Michelsen

Coronary Microvascular Function and Cardiovascular Risk Factors in Women With Angina Pectoris and No Obstructive Coronary Artery Disease: The iPOWER Study

Background The majority of women with angina‐like chest pain have no obstructive coronary artery disease when evaluated with coronary angiography. Coronary microvascular dysfunction is a possible explanation and associated with a poor prognosis. This study evaluated the prevalence of coronary microvascular dysfunction and the association with symptoms, cardiovascular risk factors, psychosocial factors, and results from diagnostic stress testing. Methods and Results After screening 3568 women, 963 women with angina‐like chest pain and a diagnostic coronary angiogram without significant coronary artery stenosis (<50%) were consecutively included. Mean age (SD) was 62.1 (9.7). Assessment included demographic and clinical data, blood samples, questionnaires, and transthoracic echocardiography during rest and high‐dose dipyridamole (0.84 mg/kg) with measurement of coronary flow velocity reserve (CFVR) by Doppler examination of the left anterior descending coronary artery. CFVR was successfully measured in 919 (95%) women. Median (IQR) CFVR was 2.33 (1.98–2.76), and 241 (26%) had markedly impaired CFVR (<2). In multivariable regression analysis, predictors of impaired CFVR were age (P<0.01), hypertension (P=0.02), current smoking (P<0.01), elevated heart rate (P<0.01), and low high‐density lipoprotein cholesterol (P=0.02), but these variables explained only a little of the CFVR variation (r 2=0.09). CFVR was not associated with chest pain characteristics or results from diagnostic stress testing. Conclusion Impaired CFVR was detected in a substantial proportion, which suggests that coronary microvascular dysfunction plays a role in the development of angina pectoris. CFVR was associated with few cardiovascular risk factors, suggesting that CFVR is an independent parameter in the risk evaluation of these women. Symptom characteristics and results from stress testing did not identify individuals with impaired CFVR.

Improving diagnosis and treatment of women with angina pectoris and microvascular disease: The iPOWER study design and rationale

BACKGROUND The iPOWER study aims at determining whether routine assessment of coronary microvascular dysfunction (CMD) in women with angina and no obstructive coronary artery disease is feasible and identifies women at risk. METHODS All women with angina referred to invasive angiographic assessment in Eastern Denmark are invited to join the study according to in- and exclusion criteria. Assessment includes demographic, clinical and psychosocial data, symptoms, electrocardiogram, blood- and urine samples and transthoracic echocardiography during rest and dipyridamol stress with measurement of coronary flow reserve (CFR) by Doppler of the left anterior descending artery. In substudies CMD will be assessed by positron emission tomography, peripheral endothelial function, magnetic resonance imaging-and computed tomography derived myocardial perfusion scans, angiographic corrected TIMI frame counts, advanced echocardiographic modalities at rest and during stress, and invasive measures of CFR and coronary vascular reactivity. The study will include 2000 women who will be followed for 5 years for cardiovascular outcomes. RESULTS By May 2013, 1685 women have been screened, 759 eligible patients identified, 530 contacted, and 299 (56%) agreed to participate. Among the first 50 patients, Doppler CFR was successfully measured in 49 (98%). CONCLUSIONS Among women with suspected ischemic heart disease and no obstructive coronary artery disease, non-invasive Doppler CFR is feasible as a routine assessment. The study will provide information on methods to diagnose CMD and determine the prognostic value of routine non-invasive assessment of microvascular function. Future study will provide women identified with CMD participation in interventional substudies designed to test treatment strategies.

Effect of the glucagon-like peptide-1 analogue liraglutide on coronary microvascular function in patients with type 2 diabetes – a randomized, single-blinded, cross-over pilot study

BackgroundImpaired coronary microcirculation is associated with a poor prognosis in patients with type 2 diabetes. In the absence of stenosis of major coronary arteries, coronary flow reserve (CFR) reflects coronary microcirculation. Studies have shown beneficial effects of glucagon-like peptide-1 (GLP-1) on the cardiovascular system. The aim of the study was to explore the short-term effect of GLP-1 treatment on coronary microcirculation estimated by CFR in patients with type 2 diabetes.MethodsPatients with type 2 diabetes and no history of coronary artery disease were treated with either the GLP-1 analogue liraglutide or received no treatment for 10 weeks, in a randomized, single-blinded, cross-over setup with a 2 weeks wash-out period. The effect of liraglutide on coronary microcirculation was evaluated using non-invasive trans-thoracic Doppler-flow echocardiography during dipyridamole induced stress. Peripheral microvascular endothelial function was assessed by Endo-PAT2000®. Interventions were compared by two-sample t-test after ensuring no carry over effect.ResultsA total of 24 patients were included. Twenty patients completed the study (15 male; mean age 57 ± 9; mean BMI 33.1 ± 4.4, mean baseline CFR 2.35 ± 0.45). There was a small increase in CFR following liraglutide treatment (change 0.18, CI95% [-0.01; 0.36], p = 0.06) but no difference in effect in comparison with no treatment (difference between treatment allocation 0.16, CI95% [-0.08; 0.40], p = 0.18). Liraglutide significantly reduced glycated haemoglobin (HbA1c) (-10.1 mmol/mol CI95% [-13.9; -6.4], p = 0.01), systolic blood pressure (-10 mmHg CI95% [-17; -3], p = 0.01) and weight (-1.9 kg CI95% [-3.6; -0.2], p = 0.03) compared to no treatment. There was no effect on peripheral microvascular endothelial function after either intervention.ConclusionsIn this short-term treatment study, 10 weeks of liraglutide treatment had no significant effect on neither coronary nor peripheral microvascular function in patients with type 2 diabetes. Further long-term studies, preferably in patients with more impaired microvascular function and using a higher dosage of GLP-1 analogues, are needed to confirm these findings.Trial registrationClinicalTrials.gov: NCT01931982.

Transthoracic Doppler echocardiography compared with positron emission tomography for assessment of coronary microvascular dysfunction: The iPOWER study

BACKGROUND Coronary microvascular function can be assessed by transthoracic Doppler echocardiography as a coronary flow velocity reserve (TTDE CFVR) and by positron emission tomography as a myocardial blood flow reserve (PET MBFR). PET MBFR is regarded the noninvasive reference standard for measuring coronary microvascular function but has limited availability. We compared TTDE CFVR with PET MBFR in women with angina pectoris and no obstructive coronary artery disease and assessed repeatability of TTDE CFVR. METHODS From a cohort of women with angina and no obstructive coronary artery stenosis at invasive coronary angiography, TTDE CFVR by dipyridamole induced stress and MBFR by rubidium-82 PET with adenosine was successfully measured in 107 subjects. Repeatability of TTDE CFVR was assessed in 10 symptomatic women and in 10 healthy individuals. RESULTS MBFR was systematically higher than CFVR. Median MBFR (interquartile range, IQR) was 2.68 (2.29-3.10) and CFVR (IQR) was 2.31 (1.89-2.72). Pearsons correlation coefficient was 0.36 (p<0.01). Limits of agreement (2·standard deviation) assessed by the Bland-Altman (confidence interval, CI) method was 1.49 (1.29;1.69) and unaffected by time-interval between examinations. Results were similar when adjusting for rate pressure product or focusing on perfusion of the left anterior descending artery region. Limits of agreement (CI) for repeated CFVR in 10 healthy individuals and in 10 women with angina was 0.44 (0.21;0.68) and 0.48 (0.22; 0.74), respectively. CONCLUSION CFVR had a good repeatability, but the agreement between CFVR and MBFR was modest. Divergence could be due to methodology differences; TTDE estimates flow velocities whereas PET estimates myocardial blood flow.

Risk Factors for Myocardial Infarction in Women and Men: A Review of the Current Literature

BACKGROUND Cardiovascular disease has been the leading cause of death in both sexes in developed countries for decades. In general, men and women share the same cardiovascular risk factors. However, in recent trials including both men and women sexspecific analyses have raised awareness of sex differences in cardiovascular risk factors due to both biological and cultural differences. RESULTS Women experience their first myocardial infarction (MI) 6-10 years later than men and a protective effect of their natural estrogen status prior to menopause has been suggested. Female sex hormones have been associated with a less atherogenic lipid profile and a more healthy fat distribution. These differences are attenuated following menopause. Regarding life style the prevalence of smoking is highest in men but female smokers have a relatively higher cardiovascular risk than male smokers. Men are more physically active than women while women have healthier dietary habits. Genetic factors also affect cardiovascular risk but no sex differences have been seen. Increased cardiovascular risk attributed to psychosocial distress is similar in men and women, but since women are more prone to psychosocial distress their burden of disease is greater. Compared with a healthy population the relative risk of MI in a diabetic population is higher in women than in men. No sex difference exists in the prevalence of hypertension but it has an earlier onset in men. CONCLUSION Sex differences in cardiovascular risk are becoming more apparent and paying attention to this is pivotal when addressing risk factors in preventive efforts.

Effect of ACE-inhibition on coronary microvascular function and symptoms in normotensive women with microvascular angina: A randomized placebo-controlled trial

Objective Studies have suggested a beneficial effect of angiotensin-converting enzyme (ACE) inhibition. To explore whether the ACE inhibitor ramipril has a direct effect on the microvasculature beyond the blood pressure (BP) lowering effect, we investigated whether ramipril improved coronary microvascular function in normotensive women with coronary microvascular dysfunction (CMD). Methods We included 63 normotensive women with angina, no epicardial stenosis>50% and CMD defined as a coronary flow velocity reserve (CFVR)<2.2 assessed by adenosine stress-echocardiography in a randomized double-blinded, superiority trial with 1:1 allocation to placebo or ramipril (maximum dose 10 mg depending on blood pressure) for 24±6 weeks. Primary outcome was CFVR. Secondary outcomes were left ventricular systolic and diastolic function and symptoms evaluated by Seattle Angina Questionnaire (clinicaltrials.gov, NCT02525081). Results Follow-up was available on 55 patients. BP remained unchanged during treatment in both groups. CFVR improved in both the ramipril (p = 0.004) and placebo group (p = 0.026) with no difference between groups (p = 0.63). Symptoms improved in both groups with no significant between-group differences. No changes were detected in parameters of systolic and diastolic function. No serious adverse reactions were reported. Conclusions In normotensive women with angina and CMD, treatment with ramipril had no significant effect on CFVR or symptoms compared with placebo. The effect of ACE inhibition previously reported may be mediated by blood pressure reduction.

Accelerated collagen turnover in women with angina pectoris without obstructive coronary artery disease: An iPOWER substudy

Aim Collagens are major cardiac extracellular matrix components, known to be actively remodelled and accumulated during diffuse myocardial fibrosis. We evaluated whether accelerated collagen turnover described by neo-epitope biomarkers reflecting collagen formation and degradation separates patients with diffuse myocardial fibrosis from asymptomatic controls. Methods and results Seventy-one women with angina pectoris without significant coronary artery disease assessed by invasive coronary angiogram were included. Competitive enzyme-linked immunosorbent assays (ELISAs) measuring circulating protein fragments in serum assessed the formation and degradation of collagen type III (Pro-C3, C3M and C3C), IV (P4NP7S and C4M), V (Pro-C5 and C5M) and VI (Pro-C6 and C6M), and degradation of collagen type I (C1M). Serum samples from 32 age-matched asymptomatic women were included as controls. Symptomatic women presented significantly elevated levels of Pro-C6, C3C, C3M, C4M and C8-C (p < 0.0001–0.0058) and significantly decreased levels of Pro-C3, C5M and C6M (p < 0.0001–0.041), reflecting accelerated collagen turnover and an imbalanced collagen formation and degradation compared to controls. Cardiac magnetic resonance T1 mapping was performed to determine extracellular volume fraction and thus diffuse myocardial fibrosis. A significant association was identified between C5M and extracellular volume fraction by cardiac magnetic resonance (p = 0.01). Conclusion Women with angina pectoris, but without significant obstructive coronary artery disease, showed an imbalanced collagen turnover compared to asymptomatic controls. The examined biomarkers are tools to monitor active collagen remodelling in patients with angina pectoris, in risk of developing myocardial fibrosis.

Treatment strategies in coronary microvascular dysfunction: a systematic review of interventional studies

CMD has been associated with a wide spectrum of diseases and conditions, and it has proven to be a strong prognostic marker of morbidity and mortality. Despite increased attention, guideline‐based treatment recommendations are lacking. We performed a systematic review of pharmacological and nonpharmacological interventions to improve coronary perfusion, assessed by IC Doppler, TTDE, PET, CMRI, transthoracic contrast perfusion echocardiography, and dilution techniques. No restrictions were made regarding the study design (randomized, placebo‐controlled/randomized with active comparators/nonrandomized with or without a control group), the cardiac condition studied, or the coronary microvascular function at baseline. An electronic database search yielded 4485 records of which 80 studies met our inclusion criteria. Included studies were sorted according to intervention and study design. Studies were small and heterogeneous in methodology, and only few were placebo‐controlled. Although some treatments looked promising, we found that no specific treatment was sufficiently well documented to be recommended in any patient groups. There is a need for larger well‐designed clinical trials, and we suggest that future studies stratify study populations according to pathogenic mechanisms, thereby investigating whether an individualized treatment approach would be more successful.

Women with Stable Angina Pectoris and No Obstructive Coronary Artery Disease: Closer to a Diagnosis

A large proportion of women with chest pain have no obstructive coronary artery disease. Recent studies have demonstrated that these women continue to have symptoms and are at increased risk of cardiovascular morbidity and mortality. Coronary microvascular dysfunction (CMD) leads to an impairment of blood flow regulation to the myocardium and possible transient ischaemia. CMD is a disease entity with several pathophysiologic aspects and diagnostic modalities continue to be developed. However, due to the complexity of the disease, it remains elusive whether CMD is the explanation for the symptoms and the poor prognosis in women with angina and no obstructive coronary artery disease.

Coronary microvascular dysfunction is not associated with a history of reproductive risk factors in women with angina pectoris—An iPOWER substudy

BACKGROUND 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. PURPOSE 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). METHODS 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. RESULTS 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/m2, and 81.5% were postmenopausal. We did not find any significant associations between any of the reproductive risk factors, Raynauds phenomenon or migraine and CFVR. CONCLUSION The lack of association between coronary microvascular function and a history of reproductive risk factors, migraine and Raynauds phenomenon suggests that a common vascular pathophysiological mechanism underlying these conditions is unlikely.