Biomarkers and Coronary Microvascular Dysfunction in Women With Angina and No Obstructive Coronary Artery Disease.

Background: Coronary microvascular dysfunction (CMD) is a major cause of ischemia with no obstructed coronary arteries. Objectives: The authors sought to assess protein biomarker signature for CMD. Methods: We quantified 184 unique cardiovascular proteins with proximity extension assay in 1,471 women with angina and no obstructive coronary artery disease characterized for CMD by coronary flow velocity reserve (CFVR) by transthoracic echo Doppler. We performed Pearson's correlations of CFVR and each of the 184 biomarkers, and principal component analyses and weighted correlation network analysis to identify clusters linked to CMD. For prediction of CMD (CFVR < 2.25), we applied logistic regression and machine learning algorithms (least absolute shrinkage and selection operator, random forest, extreme gradient boosting, and adaptive boosting) in discovery and validation cohorts. Results: Sixty-one biomarkers were correlated with CFVR with strongest correlations for renin (REN), growth differentiation factor 15, brain natriuretic protein (BNP), N-terminal-proBNP (NT-proBNP), and adrenomedullin (ADM) (all P < 1e-06). Two principal components with highest loading on BNP/NTproBNP and interleukin 6, respectively, were strongly associated with low CFVR. Weighted correlation network analysis identified 2 clusters associated with low CFVR reflecting involvement of hypertension/vascular function and immune modulation. The best prediction model for CFVR <2.25 using clinical data had area under the receiver operating characteristic curve (ROC-AUC) of 0.61 (95% CI: 0.56-0.66). ROC-AUC was 0.66 (95% CI: 0.62-0.71) with addition of biomarkers (P for model improvement = 0.01). Stringent two-layer cross-validated machine learning models had ROC-AUC ranging from 0.58 to 0.66; the most predictive biomarkers were REN, BNP, NT-proBNP, growth differentiation factor 15, and ADM. Conclusions: CMD was associated with pathways particularly involving inflammation (interleukin 6), blood pressure (REN, ADM), and ventricular remodeling (BNP/NT-proBNP) independently of clinical risk factors. Model prediction improved with biomarkers, but prediction remained moderate.

Coronary Microvascular Dysfunction: A Practical Approach to Diagnosis and Management.

PURPOSE OF REVIEW: The purpose of this review is to provide an overview of diagnostic and treatment considerations in patients with coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease (CAD). RECENT FINDINGS: The prevalence of obstructive CAD in unselected patient populations referred for evaluation of angina is less than 10%. A significant proportion of patients with angina and no obstructive CAD have CMD, a condition associated with impaired cardiovascular prognosis. Non-invasive and invasive evaluation of coronary microvascular function is feasible and widely available, yet CMD is underdiagnosed and undertreated. A patient-tailored treatment approach guided by coronary microvascular testing shows promising results for patient-reported outcomes of symptom burden and quality of life. Coronary microvascular testing should be considered in angina patients with no obstructive CAD, before other causes of chest pain are explored. A patient-tailored treatment approach guided by a complete evaluation of epicardial anatomy and macro-and microvascular function may help optimize treatment strategy and prevent unnecessary medical interventions. More research is needed to establish the long-term effect of patient-tailored therapies on risk reduction in CMD.

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.

Coronary flow velocity reserve predicts adverse prognosis in women with angina and no obstructive coronary artery disease: results from the iPOWER study.

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 < 0.001}, primarily driven by an increased risk of MI and heart failure. Results remained significant in multivariate analysis [HR 1.05 (95% CI 1.01-1.09) per 0.1 unit decrease in CFVR; P = 0.01]. In exploratory analyses, CFVR was also associated with the risk of repeated hospital admission for angina and all-cause mortality. 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.

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.

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.

Myocardial perfusion assessed with cardiac computed tomography in women without coronary heart disease.

PURPOSE: Combined coronary CT angiography and CT perfusion (CTP) is a novel, non-invasive, 'one-stop' diagnostic tool to rule out ischaemia in patients suspected for coronary artery disease (CAD). However, the normal myocardial perfusion pattern by static CTP in humans is poorly described. We aimed to investigate global and regional myocardial perfusion during rest and adenosine-induced hyperaemia in asymptomatic women without history of coronary heart disease (CHD). METHODS: Using a 320-row CT scanner with a static protocol, semi-quantitative assessment of rest and stress CTP was performed in 34 asymptomatic middle-aged women without obstructive CAD (<50% stenosis) or history of CHD, and with normal exercise stress test and left ventricular (LV) function. Using a 16-segment model, we assessed global and regional values of LV myocardial perfusion reserve (MPR) and transmural perfusion ratio (TPR). RESULTS: Mean±SD age was 56 ± 13 years. Resting and hyperaemic myocardial perfusion was heterogeneously distributed throughout the LV myocardium. During hyperaemia, global MPR increased by median (IQR) 158% (144-176) with the highest increase in the right coronary artery territory (171%; P<0.02). Rest and stress segmental TPR values ranged between 0.93-1.26 and 0.99-1.13, respectively, with the lowest values detected in the inferoseptal segments. No differences in perfusion parameters were found between participants with normal epicardial arteries and participants with non-significant epicardial atheromatosis (all P>0.05). Global perfusion parameters were not associated with age or menopausal status (all P>0.05). CONCLUSIONS: This descriptive study presents data on global and regional myocardial perfusion in a cohort of healthy middle-aged women.