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.

Left ventricular thrombus in multisystem inflammatory syndrome in children associated with COVID-19.

A 17-year-old adolescent with severe multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease-2019 developed reduced left ventricular function and left ventricular thrombus. With treatment, his condition improved and the thrombus was dissolved. This case illustrates the risk of severe intra-cardiac thrombotic complications in patients with MIS-C.

Aorta-right ventricular fistula after transcatheter aortic valve replacement.

Aortic-to-right ventricle fistula is a rare complication after transcatheter aortic valve implantation (TAVI). In this case report, an 87-year-old male was admitted with signs of congestion six weeks after TAVI. Two days later, he developed severe epigastric and back pain, elevated D-dimer, lactic acidosis and renal failure. Transthoracic echocardiography revealed a progressing aortic-to-right ventricle fistula which in retrospect had been present since the TAVI-procedure. The patient died despite supportive treatment.

Texture-based residual stress analysis of laser powder bed fused Inconel 718 parts.

Although layer-based additive manufacturing methods such as laser powder bed fusion (PBF-LB) offer an immense geometrical freedom in design, they are typically subject to a build-up of internal stress (i.e. thermal stress) during manufacturing. As a consequence, significant residual stress (RS) is retained in the final part as a footprint of these internal stresses. Furthermore, localized melting and solidification inherently induce columnar-type grain growth accompanied by crystallographic texture. Although diffraction-based methods are commonly used to determine the RS distribution in PBF-LB parts, such features pose metrological challenges in their application. In theory, preferred grain orientation invalidates the hypothesis of isotropic material behavior underlying the common methods to determine RS. In this work, more refined methods are employed to determine RS in PBF-LB/M/IN718 prisms, based on crystallographic texture data. In fact, the employment of direction-dependent elastic constants (i.e. stress factors) for the calculation of RS results in insignificant differences from conventional approaches based on the hypothesis of isotropic mechanical properties. It can be concluded that this result is directly linked to the fact that the {311} lattice planes typically used for RS analysis in nickel-based alloys have high multiplicity and less strong texture intensities compared with other lattice planes. It is also found that the length of the laser scan vectors determines the surface RS distribution in prisms prior to their removal from the baseplate. On removal from the baseplate the surface RS considerably relaxes and/or redistributes; a combination of the geometry and the scanning strategy dictates the sub-surface RS distribution.

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.

Doppler Echocardiography Assessment of Coronary Microvascular Function in Patients With Angina and No Obstructive Coronary Artery Disease.

Echocardiographic evaluation is an essential part of the diagnostic work-up in patients with known or suspected cardiovascular disease. Transthoracic Doppler echocardiography (TTDE) enables straightforward and reliable visualization of flow in the left anterior descending artery. In the absence of obstructive coronary artery disease, low TTDE-derived coronary flow velocity reserve (CFVR) is considered a marker of coronary microvascular dysfunction (CMD). TTDE CFVR is free from ionizing radiation and widely available, utilizing high-frequency transducers, pharmacologic vasodilator stress, and pulsed-wave Doppler quantification of diastolic peak flow velocities. European Society of Cardiology guidelines recommend TTDE CFVR evaluation only following preceding anatomic invasive or non-invasive coronary imaging excluding obstructive CAD. Accordingly, clinical use of TTDE CFVR is limited and CMD frequently goes undiagnosed. An evolving body of evidence underlines that low CFVR is an important and robust predictor of adverse prognosis and continuing symptoms in angina patients both with and without obstructive CAD. The majority of angina patients have no obstructive CAD, particularly among women. This has led to the suggestion that there may be a gender-specific female atherosclerotic phenotype with less epicardial obstruction, and a low CFVR signifying CMD instead. Nevertheless, available evidence indicates low CFVR is an equally important prognostic marker in both men and women. In this review, TTDE CFVR was evaluated regarding indication, practical and technical aspects, and interpretation of results. Association with symptoms and prognosis, comparison with alternative invasive and non-invasive imaging modalities, and possible interventions in angina patients with low CFVR were discussed, and key research questions were proposed.

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.

Inflammation, non-endothelial dependent coronary microvascular function and diastolic function-Are they linked?

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 CFVR<2.5. We used E/e' as an indicator of diastolic function in age-adjusted linear regressions to assess correlations between biomarkers, CFVR and diastolic function. RESULTS: CMD was found in 59% of participants whereas only 4% fulfilled strict criteria for diastolic dysfunction. Thirty-five biomarkers, 17 of them inflammatory, were negatively correlated with CFVR and 25, 15 inflammatory, were positively correlated with E/e'. A total of 13 biomarkers, 9 inflammatory, were associated with both CFVR and E/e'. CFVR and E/e' were only correlated in the subgroup of patients with CMD and signs of increased filling pressure (E/e'>10) (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.

Prognosis and Reclassification by YKL-40 in Stable Coronary Artery Disease.

Background The inflammatory biomarker YKL-40 has previously been studied as a potential risk marker in cardiovascular disease. We aimed to assess the prognostic reclassification potential of serum YKL-40 in patients with stable coronary artery disease. Methods and Results The main study population was the placebo group of the CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) trial. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. We used Cox proportional hazards regression models adjusted for C-reactive protein level and baseline cardiovascular risk factors. Improvement in prediction by adding serum YKL-40 to the risk factors was calculated using the Cox-Breslow method and c-statistic. A total of 2200 patients were randomized to placebo, with a follow-up duration of 10 years. YKL-40 was associated with an increased risk of the composite outcome (hazard ratio per unit increase in (YKL-40) 1.13, 95% CI 1.03-1.24, P=0.013) and all-cause mortality (hazard ratio 1.32, 95% CI 1.17-1.49, P<0.0001). Considering whether a composite-outcome event was more likely to have, or not have, occurred to date, we found 68.4% of such predictions to be correct when based on the standard predictors, and 68.5% when serum YKL-40 was added as a predictor. Equivalent results were obtained with c-statistics. Conclusions Higher serum YKL-40 was independently associated with an increased risk of adverse cardiovascular outcomes and mortality. Addition of YKL-40 did not improve risk prediction in patients with stable coronary artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00121550.

Recurrent event survival analysis predicts future risk of hospitalization in patients with paroxysmal and persistent atrial fibrillation.

BACKGROUND: In patients with paroxysmal atrial fibrillation (PAF) or persistent atrial fibrillation (PeAF) symptom burden and fear of hospital readmission are major causes of reduced quality of life. We attempted to develop a prediction model for future atrial fibrillation hospitalization (AFH) risk in PAF and PeAF patients including all previously experienced AFHs in the analysis, as opposed to time to first event. METHODS: Recurrent event survival analysis was used to model the impact of past AFHs on the risk of future AFHs. A recurrent event was defined as a hospitalization due to a new episode of AF. Death or progression to permanent AF were included as competing risks. RESULTS: We enrolled 174 patients with PAF or PeAF, mean follow up duration was 1279 days, and 325 AFHs were observed. Median patient age was 63.0 (IQR 52.2-68.0), 29% had PAF, and 71% were male. Highly significant predictors of future AFH risk were PeAF (HR 3.20, CI 2.01-5.11) and number of past AFHs observed (HR for 1 event: 2.97, CI 2.04-4.32, HR for ≥2 events: 7.54, CI 5.47-10.40). CONCLUSION: In PAF and PeAF patients, AF type and observed AFH frequency are highly significant predictors of future AFH risk. The developed model enables risk prediction in individual patients based on AFH history and baseline characteristics, utilizing all events experienced by the patient. This is the first time recurrent event survival analysis has been used in AF patients.

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.

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.