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.

Vital exhaustion in women with chest pain and no obstructive coronary artery disease: the iPOWER study.

BACKGROUND: More 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. METHODS: Prevalence 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. FINDINGS: Median (IQR) VE score was 4 (1-9) and 2 (0-5) in symptomatic and asymptomatic women, respectively (age adjusted, p<0.001). The risk of severe VE was significantly higher in symptomatic women compared with asymptomatic women (OR 3.3, 95% CI 2.5 to 4.4), independent of age and risk factors, and was associated with symptom severity. VE and depression scores were correlated but principal component cluster analysis (PCCA) showed clear distinctiveness between the two constructs. CONCLUSIONS: Women 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 IMPLICATIONS: Mental 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.

Evaluation of computed tomography myocardial perfusion in women with angina and no obstructive coronary artery disease.

Women with angina and no obstructive coronary artery disease (CAD) have worse cardiovascular prognosis than asymptomatic women. Limitation in myocardial perfusion caused by coronary microvascular dysfunction (CMD) is one of the proposed mechanisms contributing to the adverse prognosis. The aim of this study was to assess myocardial perfusion in symptomatic women with no obstructive CAD suspected for CMD compared with asymptomatic sex-matched controls using static CT perfusion (CTP). We performed a semi-quantitative assessment of the left ventricular myocardial perfusion and myocardial perfusion reserve (MPR), using static CTP with adenosine provocation, in 105 female patients with angina and no obstructive CAD (< 50% stenosis) and 33 sex-matched controls without a history of angina or ischemic heart disease.  Patients were on average 4 years older (p = 0.04) and had a higher burden of cardiovascular risk factors. While global perfusion during rest was comparable between the groups (age-adjusted p = 0.12), global perfusion during hyperemia was significantly reduced in patients compared with controls (163 ± 23 HU vs. 171 ± 25 HU; age-adjusted p = 0.023). The ability to increase myocardial perfusion during adenosine-induced vasodilation was significantly diminished in patients (MPR 148% vs. 158%; age-adjusted p < 0.001). This remained unchanged after adjustment for cardiovascular risk factors (p = 0.008). Women with angina and no obstructive CAD have reduced hyperemic myocardial perfusion and MPR compared with sex-matched controls. Impaired myocardial perfusion may be related to the presence of CMD in some of these women.

Cardiac Magnetic Resonance Imaging used for Evaluation of Adipose-Derived Stromal Cell Therapy in Patients with Chronic Ischemic Heart Disease.

Adipose-derived stromal cell (ASC) therapy is currently investigated as a new treatment option for patients with ischemic heart disease (IHD). The aim of this study was to evaluate the effect of ASC therapy in patients with chronic IHD measuring myocardial perfusion and cardiac function using cardiac magnetic resonance imaging (CMRI). Patients were included in MyStromalCell trial, a phase II, randomized, double-blinded, placebo-controlled study investigated the effect of ASCs in patients with chronic IHD with preserved left ventricular ejection fraction (LVEF). In total, 41 of 60 patients underwent cine, late enhancement, rest and stress imaging with CMRI. There was a non-significant difference between stress and rest values in maximal signal intensity, a measure of myocardial perfusion, from baseline to follow-up comparing placebo with ASC group (-52.52 ± 88.61 and 3.05 ± 63.17, p = 0.061, respectively). LVEF, myocardial mass, stroke volume, left ventricle end-diastolic volume and end-systolic volume changed non-significantly (-0.5 ± 4.7%, -3.5 ± 13.1 g, -0.7 ± 8.6 mL, 1.9 ± 25.1 mL and 2.6 ± 16.5 mL, respectively) in the placebo group and in the ASC group (0.7 ± 8.6%, 0.9 ± 10.8 g, -0.3 ± 26.1 mL, -3.0 ± 31.5 mL and -2.7 ± 20.4 mL, respectively) from baseline to 6 months follow-up. The amount of scar tissue was unchanged in the placebo group by 0.0 ± 1.6 g, p = 1.0 and in the ASC group with -0.3 ± 2.3 g, p = 0.540. There was no difference between the groups. There was a non-significant trend toward increased myocardial perfusion but no significant changes in functional parameters or amount of scar tissue in patients treated with ASCs compared with patients allocated into the placebo group.

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.

Coronary microvascular dysfunction is associated with cardiac time intervals in women with angina and no obstructive coronary artery disease: An iPOWER substudy.

BACKGROUND: Coronary microvascular dysfunction (CMD) may cause angina in the absence of obstructive coronary artery disease (CAD) and increases the risk of future adverse cardiovascular events. Transthoracic Doppler echocardiography (TTDE) with pharmacological stress can assess coronary flow velocity reserve (CFVR), a measure of coronary microvascular function. However, simpler methods would be preferable for diagnosing CMD. Therefore, we examined the relationship between CFVR and cardiac time intervals measured by TTDE in a cohort of women with angina and no obstructive CAD. METHODS: In a prospective cohort study, we included 389 women with angina, left ventricular ejection fraction > 45%, and no obstructive CAD. CMD was defined as CFVR < 2.0. The study population was divided into three groups according to cutoff values of CFVR < 2, 2 ≤ CFVR ≤ 2.5, and CFVR > 2.5. Isovolumic contraction time (IVCT), ejection time (ET), and isovolumic relaxation time (IVRT) were measured by tissue Doppler M-mode, and the myocardial performance index (MPI = (IVCT + IVRT)/ET) was calculated. RESULTS: Coronary microvascular dysfunction was associated with increasing age, hypertension, higher resting heart rate, and lower diastolic blood pressure. Moreover, CMD was associated with higher E/e' ratio (P = 0.002) and longer IVCT (P < 0.001), higher MPI (P < 0.001) and shorter ET (P = 0.002), but not with IVRT or conventional measures of left ventricular geometry, mass, and function. In multivariable analysis, longer IVCT (P < 0.001) and higher MPI (P = 0.002) remained associated with CMD. CONCLUSION: In women with angina and no obstructive CAD, CMD is associated with longer IVCT and higher MPI indicating a link between CMD and subtle alternations of systolic and combined measures of cardiac time intervals.

Myocardial first pass perfusion assessed by cardiac magnetic resonance and coronary microvascular dysfunction in women with angina and no obstructive coronary artery disease.

Coronary microvascular dysfunction (CMD) is associated with a poor prognosis even in absence of obstructive coronary artery disease. CMD can be assessed as a myocardial blood flow reserve by positron emission tomography (PETMBFR) and as coronary flow velocity reserve by transthoracic Doppler echocardiography (TTDECFVR). Impaired first-pass perfusion assessed by cardiac magnetic resonance (CMR) is an early sign of ischemia. We aimed to investigate the association between CMD and CMR first-pass perfusion. Women (n = 66) with angina pectoris and an invasive coronary angiogram (<50% stenosis) were assessed by TTDECFVR and in a subgroup of these (n = 54) also by PETMBFR. Semi-quantitative evaluation of first-pass perfusion at rest and adenosine stress was assessed by gadolinium CMR in all 66 women. Four measures of CMR perfusion reserve were calculated using contrast upslope, maximal signal intensity and both indexed to arterial input. Mean (standard deviation) age was 62 (8) years. Median (interquartile range) TTDECFVR was 2.3 (1.8;2.7) and PETMBFR was 2.7 (2.2;3.1). Using a cut-off of 2.0 for TTDECFVR and 2.5 for PETMBFR, 25 (38%) and 21 (39%) had CMD, respectively. CMR myocardial perfusion reserve from contrast upslope (CMR_MPRupslope) showed moderate but significant correlation with PETMBFR (R = .46, p < .001) while none of the other CMR variables were associated with CMD. A CMR_MPRupslope cut-off of 0.78 identified CMD, area under the curve 0.73 (p = .001). The results indicate that CMR_MPRupslope may be associated to PETMBFR; a measure of CMD. Further research is needed to validate and implement the use of CMR first pass perfusion in this population.

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.

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, Raynaud's phenomenon or migraine and CFVR. CONCLUSION: The 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.

Ventricular repolarization alterations in women with angina pectoris and suspected coronary microvascular dysfunction.

OBJECTIVES: CMD could be the explanation of angina pectoris with no obstructive CAD and may cause ventricular repolarization changes. We compared T-wave morphology and QTc interval in women with angina pectoris with a control group as well as the associations with CMD. METHODS: Women with angina pectoris and no obstructive coronary artery disease (n=138) and age-matched controls were compared in regard to QTc interval and morphology combination score (MCS) based on T-wave asymmetry, flatness and presence of T-wave notch. CMD was assessed as a coronary flow velocity reserve (CFVR) by transthoracic echocardiography. RESULTS: Women with angina pectoris had significantly longer QTc intervals (429±20ms) and increased MCS (IQR) (0.73 [0.64-0.80]) compared with the controls (419±20ms) and (0.63 [(0.53-0.73]), respectively (both p<0.001). CFVR was associated with longer QTc interval (p=0.02), but the association was attenuated after multivariable adjustment (p=0.08). CONCLUSION: This study suggests that women with angina pectoris have alterations in T-wave morphology as well as longer QTc interval compared with a reference population. CMD might be an explanation.

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.

Adipose-Derived Stromal Cells for Treatment of Patients with Chronic Ischemic Heart Disease (MyStromalCell Trial): A Randomized Placebo-Controlled Study.

We aimed to evaluate the effect of intramyocardial injections of autologous VEGF-A165-stimulated adipose-derived stromal cells (ASCs) in patients with refractory angina. MyStromalCell trial is a randomized double-blind placebo-controlled study including sixty patients with CCS/NYHA class II-III, left ventricular ejection fraction > 40%, and at least one significant coronary artery stenosis. Patients were treated with ASC or placebo in a 2 : 1 ratio. ASCs from the abdomen were culture expanded and stimulated with VEGF-A165. At 6 months follow-up, bicycle exercise tolerance increased significantly in time duration 22 s (95%CI -164 to 208 s) (P = 0.034), in watt 4 (95%CI -33 to 41, 0.048), and in METs 0.2 (95%CI -1.4 to 1.8) (P = 0.048) in the ASC group while there was a nonsignificant increase in the placebo group in time duration 9 s (95%CI -203 to 221 s) (P = 0.053), in watt 7 (95%CI -40 to 54) (P = 0.41), and in METs 0.1 (95%CI -1.7 to 1.9) (P = 0.757). The difference between the groups was not significant (P = 0.680, P = 0.608, and P = 0.720 for time duration, watt, and METs, resp.). Intramyocardial delivered VEGF-A165-stimulated ASC treatment was safe but did not improve exercise capacity compared to placebo. However, exercise capacity increased in the ASC but not in the placebo group. This trial is registered with ClinicalTrials.gov NCT01449032.

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). Pearson's 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.

Coronary microvascular function and myocardial fibrosis in women with angina pectoris and no obstructive coronary artery disease: the iPOWER study.

BACKGROUND: Even in absence of obstructive coronary artery disease women with angina pectoris have a poor prognosis possibly due to coronary microvascular disease. Coronary microvascular disease can be assessed by transthoracic Doppler echocardiography measuring coronary flow velocity reserve (CFVR) and by positron emission tomography measuring myocardial blood flow reserve (MBFR). Diffuse myocardial fibrosis can be assessed by cardiovascular magnetic resonance (CMR) T1 mapping. We hypothesized that coronary microvascular disease is associated with diffuse myocardial fibrosis. METHODS: Women with angina, a clinically indicated coronary angiogram with <50 % stenosis and no diabetes were included. CFVR was measured using dipyridamole (0.84 mg/kg) and MBFR using adenosine (0.84 mg/kg). Focal fibrosis was assessed by 1.5 T CMR late gadolinium enhancement (0.1 mmol/kg) and diffuse myocardial fibrosis by T1 mapping using a modified Look-Locker pulse sequence measuring T1 and extracellular volume fraction (ECV). RESULTS: CFVR and CMR were performed in 64 women, mean (SD) age 62.5 (8.3) years. MBFR was performed in a subgroup of 54 (84 %) of these women. Mean native T1 was 1023 (86) and ECV (%) was 33.7 (3.5); none had focal fibrosis. Median (IQR) CFVR was 2.3 (1.9; 2.7), 23 (36 %) had CFVR < 2 indicating coronary microvascular disease, and median MBFR was 2.7 (2.2; 3.0) and 19 (35 %) had a MBFR value below 2.5. No significant correlations were found between CFVR and ECV or native T1 (R 2 = 0.02; p = 0.27 and R 2 = 0.004; p = 0.61, respectively). There were also no correlations between MBFR and ECV or native T1 (R 2 = 0.1; p = 0.13 and R 2 = 0.004, p = 0.64, respectively). CFVR and MBFR were correlated to hypertension and heart rate. CONCLUSION: In women with angina and no obstructive coronary artery disease we found no association between measures of coronary microvascular disease and myocardial fibrosis, suggesting that myocardial ischemia induced by coronary microvascular disease does not elicit myocardial fibrosis in this population. The examined parameters seem to provide independent information about myocardial and coronary disease.

Mesenchymal stromal cell therapy in ischemic heart disease.

Although, treatment of ischemic heart disease (IHD) has improved considerably within the last decades, it is still the main cause of death worldwide. Despite maximum treatment, many IHD patients suffer from refractory angina and heart failure, which severely limits their daily lives. Moreover, IHD is very costly for the health care system. Therefore, new treatment options and strategies are being researched intensely. Stem cell therapy to improve myocardial perfusion and stimulate growth of new cardiomyocytes could be a new way to go. Nevertheless, the results from clinical studies have varied considerably, probably due to the use of many different cell lines obtained from different tissues and the different patient populations. The present review will focus on treatment with the mesenchymal stromal cell from bone marrow and adipose tissue in animal and patients with acute and chronic IHD (CIHD).

Peripheral Reactive Hyperemia Index and Coronary Microvascular Function in Women With no Obstructive CAD: The iPOWER Study.

OBJECTIVES: This study investigated whether digital reactive hyperemia index (RHI) measured by digital pulse amplitude tonometry is a sensitive indicator of coronary microvascular dysfunction (CMD). BACKGROUND: CMD is an early marker of cardiovascular disease. However, CMD is a complex diagnosis and consists of multiple abnormalities of the coronary circulation. Impaired RHI is a noninvasive measure of peripheral vascular dysfunction that can identify individuals with acetylcholine induced coronary vascular dysfunction. It is largely unknown whether there is also an association between RHI and the endothelial-independent aspect of CMD assessed as a coronary flow velocity reserve (CFVR). METHODS: We included 339 women with chest pain suggestive of angina pectoris and a diagnostic invasive coronary angiogram without significant coronary artery stenosis (<50%). CFVR was measured by transthoracic pulsed wave Doppler echocardiography during dipyridamole infusion (0.84 mg/kg). RHI was assessed by digital pulse amplitude tonometry. Participants were categorized in 3 RHI and 3 CFVR groups. We examined the association between CFVR and RHI and the distribution of cardiovascular risk factors between the CFVR and RHI groups. RESULTS: CFVR and RHI were successfully measured in 322 participants. Median CFVR was 2.3 (interquartile range: 2.0 to 2.8) and median RHI was 2.1 (interquartile range: 1.6 to 2.6). No correlation was found between CFVR and RHI (Spearman's rho = -0.067, p = 0.23), and mean RHI did not differ between CFVR categories (p = 0.39). Participants with low CFVR were significantly older and had a significantly greater burden of hypertension, whereas participants with an impaired RHI had a higher body mass index and were more likely to have diabetes and be current smokers. CONCLUSIONS: RHI does not identify individuals with CMD assessed as impaired CFVR by dipyridamole stress echocardiography in women with no obstructive coronary artery disease. The two methods are likely to identify different aspects of vascular pathology, as indicated by the different association with cardiovascular risk factors.

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.

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.

The inflammatory biomarker YKL-40 decreases stepwise after exercise stress test.

BACKGROUND: Serum YKL-40 is an inflammatory biomarker associated with disease activity and mortality in diseases characterized by inflammation such as coronary artery disease (CAD). Exercise has a positive effect on CAD, possibly mediated by a decreased inflammatory activity. This study aimed to compare serial measurements of serum YKL-40 before and after exercise in patients with stable CAD versus controls. MATERIALS AND METHODS: Eleven patients with stable CAD verified by coronary angiography (>70% stenosis) and 11 patients with a computer tomography angiography with no stenosis or calcification (calcium score=0) (controls) performed a standard clinical maximal exercise test. Serum YKL-40 was measured before exercise, immediately after exercise, and every hour for 6 h. RESULTS: Cardiovascular risk factors were more prevalent among the CAD patients compared with the controls. CAD patients had higher serum concentration of YKL-40 at baseline compared with controls, median (interquartile range) 94 (52-151) versus 57 (45-79) µg/l. Serum YKL-40 decreased stepwise after exercise, with a median decrease of 16 (13-39) µg/l for the CAD patients and 13 (10-22) µg/l for the controls from baseline to the lowest value. Thereafter, values increased again toward baseline level. Time after exercise was a significant factor for decrease in serum YKL-40 (P<0.0001), but no difference in YKL-40 decrease over time could be demonstrated between the groups (P=0.12). CONCLUSION: Serum YKL-40 is elevated in patients with documented CAD compared with controls, and it decreases stepwise after exercise in both groups, indicating an anti-inflammatory effect of exercise independent of the presence of coronary atherosclerosis.