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Purpose Systemic 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. Methods In 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 CFVR10) (p = 0.012). Conclusion This 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.

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.

Aims: Coronary vascular dysfunction is linked with poor cardiovascular prognosis in patients without obstructive coronary artery disease (CAD) but a critical appraisal of the literature is lacking. Methods and results: We performed a systematic review and meta-analysis to quantify the cardiovascular risk associated with endothelial dependent and non-endothelial dependent coronary vascular dysfunction in patients with normal or non-obstructive CAD (epicardial stenosis < 50%). Prospective cohort studies that reported coronary vascular dysfunction at baseline and cardiovascular outcomes at follow-up were included. We identified 52 papers of which 26 were included in the meta-analyses. Study populations included stable angina (n = 15), heart failure (n = 4), diabetes (n = 2), hypertrophic obstructive cardiomyopathy (n = 2), chronic kidney disease, aortic stenosis and left atrial enlargement (each n = 1): RR estimates were similar in patients with stable angina and other patient groups. For epicardial endothelial dependent dysfunction (six studies, 243 events in 1192 patients) the summarized RR was 2.38 (95% confidence intervals (95% CI) 1.74–3.25), for non-endothelial dependent dysfunction assessed as coronary flow velocity reserve (CFVR) by echocardiography (10 studies, 428 events in 5134 patients) RR was 4.58 (95% CI 3.58–5.87) and for coronary flow reserve (CFR) by PET (10 studies, 538 events in 3687 patients) RR was 2.44 (95% CI 1.80–3.30). However, RR estimates were robust in a series of sensitivity analyses. Conclusion: The presence of coronary vascular dysfunction in patients with normal or non-obstructive CAD predicts adverse cardiovascular outcome. Multicentre studies and uniform guidelines for assessing coronary vascular dysfunction are encouraged.

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.

OBJECTIVE: The construct of vital exhaustion has been identified as a potential independent psychological risk factor for incident and recurrent coronary heart disease (CHD). Despite several decades of research, no systematic review or meta-analysis has previously attempted to collate the empirical evidence in this field. The purpose of this study was to review and quantify the impact of vital exhaustion on the development and progression of CHD.METHODS: Prospective and case-control studies reporting vital exhaustion at baseline and CHD outcomes at follow-up were derived from PubMed, PsycINFO (1980 to July 2015; articles in English and published articles only), and bibliographies. Information on aim, study design, sample size, inclusion and exclusion criteria, assessment methods of psychological risk factors, and results of crude and adjusted regression analyses were abstracted independently by two authors.RESULTS: Thirteen prospective (n = 52,636) and three case-control (cases, n = 244; controls, n = 457) studies assessed vital exhaustion and could be summarized in meta-analyses. The pooled adjusted risk of CHD in healthy populations was 1.50 (95% confidence interval [CI] = 1.22-1.85) for prospective studies, and 2.61 (95% CI = 1.66-4.10) for case-control studies using hospital controls. Risk of recurrent events in patients with CHD was 2.03 (95% CI = 1.54-2.68). The pooled adjusted risk of chronic heart failure in healthy populations was 1.37 (95% CI = 1.21-1.56), but this was based on results from only two studies.CONCLUSIONS: Vital exhaustion is associated with increased risk of incident and recurrent CHD.

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.

Pulmonary hyperinflation attained by glossopharyngeal insufflation (GPI) challenges the circulation by compressing the heart and pulmonary vasculature. Our aim was to determine the amount of blood translocated from the central blood volume during GPI. Cardiac output and cardiac chamber volumes were assessed by magnetic resonance imaging in twelve breath-hold divers at rest and during apnea with GPI. Pulmonary blood volume was determined from pulmonary blood flow and transit times for gadolinium during first-pass perfusion after intravenous injection. During GPI, the lung volume increased by 0.8±0.6L (11±7%) above the total lung capacity. All cardiac chambers decreased in volume and despite a heart rate increase of 24±29 bpm (39±50%), pulmonary blood flow decreased by 2783±1820mL (43±20%). The pulmonary transit time remained unchanged at 7.5±2.2s and pulmonary blood volume decreased by 354±176mL (47±15%). In total, central blood volume decreased by 532±248mL (46±14%). Voluntary pulmonary hyperinflation leads to ∼50% decrease in pulmonary and central blood volume.

BACKGROUND: Coronary flow velocity reserve (CFVR) measured by transthoracic Doppler echocardiography is a noninvasive measure of microvascular function, but it has not achieved widespread use, mainly because of concerns of validity and feasibility. The aim of this study was to describe the feasibility and factors associated with the quality of CFVR obtained in a large prospective study of women suspected of having microvascular disease.METHODS: Women with angina-like chest pain and no obstructive coronary artery disease on coronary angiography (<50% stenosis) were consecutively examined by transthoracic Doppler echocardiography of the left anterior descending coronary artery to measure CFVR (n = 947). Quality was evaluated on the basis of (1) identification of the left anterior descending coronary artery, (2) maintained probe position throughout the examination, (3) visibility and configuration of the left anterior descending coronary artery in two-dimensional color Doppler mode, and (4) gradual, consistent increases of characteristic, well-defined flow velocity curves in pulsed-wave mode.RESULTS: The mean age (SD) was 62.1 ± 9.7 years. On the basis of the evaluations, patients were divided into four groups according to quality score: nonfeasible (n = 28 [3%]), low quality (n = 80 [8%]), medium quality (n = 451 [48%]), and high quality (n = 388 [41%]). Quality score was associated with diabetes (P < .01), body mass index (P = .02), waist circumference (P = .05), nonsignificant atherosclerosis on coronary angiography (P = .03), and operator experience (P < .01). Low examination quality was associated with lower CFVR (P = .03), also after multivariate adjustment.CONCLUSIONS: Transthoracic Doppler echocardiographic measurement of CFVR is highly feasible and of good quality in experienced hands. However, CFVR is possibly underestimated when examination quality is low. Awareness of pitfalls and potential bias may improve the validity and

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.

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

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 is