Chronic infarct size after spontaneous coronary artery dissection: implications for pathophysiology and clinical management.

AIMS: To report the extent and distribution of myocardial injury and its impact on left ventricular systolic function with cardiac magnetic resonance imaging (CMR) following spontaneous coronary artery dissection (SCAD) and to investigate predictors of myocardial injury. METHODS AND RESULTS: One hundred and fifty-eight angiographically confirmed SCAD-survivors (98% female) were phenotyped by CMR and compared in a case-control study with 59 (97% female) healthy controls (44.5 ± 8.4 vs. 45.0 ± 9.1 years). Spontaneous coronary artery dissection presentation was with non-ST-elevation myocardial infarction in 95 (60.3%), ST-elevation myocardial infarction (STEMI) in 52 (32.7%), and cardiac arrest in 11 (6.9%). Left ventricular function in SCAD-survivors was generally well preserved with small reductions in ejection fraction (57 ± 7.2% vs. 60 ± 4.9%, P < 0.01) and increases in left ventricular dimensions (end-diastolic volume: 85 ± 14 mL/m2 vs. 80 ± 11 mL/m2, P < 0.05; end-systolic volume: 37 ± 11 mL/m2 vs. 32 ± 7 mL/m2, P <0.01) compared to healthy controls. Infarcts were small with few large infarcts (median 4.06%; range 0-30.9%) and 39% having no detectable late gadolinium enhancement (LGE). Female SCAD patients presenting with STEMI had similar sized infarcts to female Type-1 STEMI patients age <75 years. Multivariate modelling demonstrated STEMI at presentation, initial TIMI 0/1 flow, multivessel SCAD, and a Beighton score >4 were associated with larger infarcts [>10% left ventricular (LV) mass]. CONCLUSION: The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fraction. Patients presenting with STEMI, TIMI 0/1 flow, multivessel SCAD and those with features of connective tissue disorders are more likely to have larger infarcts.

Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses.

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the active form of vitamin D, exerts potent effects on several tissues including cells of the immune system, where it affects T cell activation, differentiation and migration. The circulating, inactive form of vitamin D, 25(OH)D(3), is generally used as an indication of vitamin D status. However, use of this precursor depends on its uptake by cells and subsequent conversion by the enzyme 25(OH)D(3)-1α-hydroxylase (CYP27B1) into active 1,25(OH)(2)D(3). Using human T cells, we show in this study that addition of inactive 25(OH)D(3) is sufficient to alter T cell responses only when dendritic cells (DCs) are present. Mechanistically, CYP27B1 is induced in DCs upon maturation with LPS or upon T cell contact, resulting in the generation and release of 1,25(OH)(2)D(3), which subsequently affects T cell responses. In most tissues, vitamin D binding protein acts as a carrier to enhance the use of vitamin D. However, we show that vitamin D binding protein modulates T cell responses by restricting the availability of inactive 25(OH)D(3) to DC. These data indicate that the level of free 25(OH)D(3) available to DCs determines the inflammatory/regulatory balance of ensuing T cell responses.

Hemostatic disorders in patients with infective endocarditis undergoing urgent surgical valve replacement - Rethinking current beliefs.

BACKGROUND: Although infective endocarditis (IE) represents a unique model of thrombo-inflammatory disease, the most frequent early complications of surgical valve replacement (SVR) in IE population are coagulopathy and bleeding. The hemostatic capacity and procedure-related coagulation disorders of IE patients undergoing SVR are unknown. The aims of this study were to test periprocedural hemostasis in IE patients undergoing urgent SVR, and to assess the association between disorders of hemostasis and early bleeding as well as with thromboembolic events. METHODS: A prospective, two-center, hypothesis generating, observational study was performed between Dec 2017 and Jan 2020. Periprocedural hemostasis of IE patients was assessed using Total Thrombus-formation Analysis System (T-TAS Plus) within 24 h before and 72 h post SVR. RESULTS: Overall, 25 patients with active IE undergoing urgent SVR were tested. Hemostatic capacity of IE patients was significantly impaired pre-SVR as well as post-SVR compared to normal values, in most aspects of T-TAS assays under high and low shear forces, including prolonged activation of coagulation (T10), final clot formation (OT) and clot strength (AUC30). Post-SVR T-TAS results were significantly associated with early bleeding and with red blood cell, platelet, and fresh frozen plasma administration. No association with thrombo-embolic events was found. CONCLUSIONS: Patients with active IE undergoing urgent SVR have significantly reduced hemostatic capacity before and after SVR. Hemostatic insufficiency post-SVR is related to bleeding and blood products transfusion. T-TAS may be helpful in assessment of periprocedural hemostasis in patients with IE undergoing SVR.

PHACTR1 modulates vascular compliance but not endothelial function: a translational study.

AIMS: The non-coding locus at 6p24 located in Intron 3 of PHACTR1 has consistently been implicated as a risk allele in myocardial infarction and multiple other vascular diseases. Recent murine studies have identified a role for Phactr1 in the development of atherosclerosis. However, the role of PHACTR1 in vascular tone and in vivo vascular remodelling has yet to be established. The aim of this study was to investigate the role of PHACTR1 in vascular function. METHODS AND RESULTS: Prospectively recruited coronary artery disease (CAD) patients undergoing bypass surgery and retrospectively recruited spontaneous coronary artery dissection (SCAD) patients and matched healthy volunteers were genotyped at the PHACTR1 rs9349379 locus. We observed a significant association between the PHACTR1 loci and changes in distensibility in both the ascending aorta (AA = 0.0053 ± 0.0004, AG = 0.0041 ± 0.003, GG = 0.0034 ± 0.0009, P < 0.05, n = 58, 54, and 7, respectively) and carotid artery (AA = 12.83 ± 0.51, AG = 11.14 ± 0.38, GG = 11.69 ± 0.66, P < 0.05, n = 70, 65, and 18, respectively). This association was not observed in the descending aorta or in SCAD patients. In contrast, the PHACTR1 locus was not associated with changes in endothelial cell function with no association between the rs9349379 locus and in vivo or ex vivo vascular function observed in CAD patients. This finding was confirmed in our murine model where the loss of Phactr1 on the pro-atherosclerosis ApoE-/- background did not alter ex vivo vascular function. CONCLUSION: In conclusion, we have shown a role for PHACTR1 in arterial compliance across multiple vascular beds. Our study suggests that PHACTR1 has a key structural role within the vasculature.

Sex- and age-specific normal values for automated quantitative pixel-wise myocardial perfusion cardiovascular magnetic resonance.

AIMS: Recently developed in-line automated cardiovascular magnetic resonance (CMR) myocardial perfusion mapping has been shown to be reproducible and comparable with positron emission tomography (PET), and can be easily integrated into clinical workflows. Bringing quantitative myocardial perfusion CMR into routine clinical care requires knowledge of sex- and age-specific normal values in order to define thresholds for disease detection. This study aimed to establish sex- and age-specific normal values for stress and rest CMR myocardial blood flow (MBF) in healthy volunteers. METHODS AND RESULTS: A total of 151 healthy volunteers recruited from two centres underwent adenosine stress and rest myocardial perfusion CMR. In-line automatic reconstruction and post processing of perfusion data were implemented within the Gadgetron software framework, creating pixel-wise perfusion maps. Rest and stress MBF were measured, deriving myocardial perfusion reserve (MPR) and were subdivided by sex and age. Mean MBF in all subjects was 0.62 ± 0.13 mL/g/min at rest and 2.24 ± 0.53 mL/g/min during stress. Mean MPR was 3.74 ± 1.00. Compared with males, females had higher rest (0.69 ± 0.13 vs. 0.58 ± 0.12 mL/g/min, P < 0.01) and stress MBF (2.41 ± 0.47 vs. 2.13 ± 0.54 mL/g/min, P = 0.001). Stress MBF and MPR showed significant negative correlations with increasing age (r = -0.43, P < 0.001 and r = -0.34, P < 0.001, respectively). CONCLUSION: Fully automated in-line CMR myocardial perfusion mapping produces similar normal values to the published CMR and PET literature. There is a significant increase in rest and stress MBF, but not MPR, in females and a reduction of stress MBF and MPR with advancing age, advocating the use of sex- and age-specific reference ranges for diagnostic use.

Variability of sputum inflammatory mediators in COPD and α1-antitrypsin deficiency.

There is inherent daily variability of sputum inflammatory mediators in stable-state patients with usual chronic obstructive pulmonary disease (COPD). The variability of pulmonary inflammation in patients with α(1)-antitrypsin deficiency (A1ATD) is unknown. Our study aimed to quantify this variability, in comparison to patients with usual COPD, in order to facilitate power calculations for proof of concept trials of putative specific anti-inflammatory agents in both groups. Sputum interleukin (IL)-8, myeloperoxidase (MPO), leukotriene B(4) (LTB(4)) and differential cell counts were measured in 12 usual COPD patients and 12 A1ATD patients on nine occasions over a 1-month period. All samples were obtained in the stable clinical state. There was significant daily variability in all mediators in all patients. A1ATD patients had higher sputum concentrations of IL-8 and LTB(4) compared with usual COPD, but lower levels of MPO and absolute neutrophil counts. Patients with usual COPD had more intra-patient variability, A1ATD patients demonstrated greater inter-patient variability. There are increased concentrations of pulmonary inflammatory mediators but fewer sputum neutrophils in A1ATD compared with usual COPD. The daily variability of inflammatory mediators and cell counts was significantly reduced in both groups by averaging sequential samples. This can be utilised to perform power calculations for future proof of concept studies; averaging three sequential samples appears optimum.

A novel model and molecular therapy for Z alpha-1 antitrypsin deficiency.

Animal models that closely resemble human disease can present a challenge. Particularly so in alpha-1 antitrypsin deficiency (α(1)ATD), as the mouse alpha-1 antitrypsin (α(1)AT) cluster encodes five highly related genes compared with the one in humans. The mouse PI2 homologue is closest to the α(1)AT human gene. We have changed the equivalent mouse site that results in the Z variant in man (Glu342Lys) and made both the "M" and "Z" mouse PI2 α(1)AT proteins. We have tested the ability of a small-molecular-weight compound CG to alleviate polymerisation of these mouse α(1)AT proteins as it has been shown to reduce aggregates of Z α(1)AT in man. We found that (1) CG specifically reduces the formation of polymers of recombinant mouse "Z" protein but not "M" protein; (2) whereas there is significantly more α(1)AT secreted from Chinese Hamster Ovary cells transfected with the mouse "M" α(1)AT gene than with the "Z" (20.8 ± 3.9 and 6.7 ± 3.6, respectively; P < 0.005), CG increased the α(1)AT levels secreted from "Z" cells (21.2 ± 0.01) to that of "M" (20.2 ± 0.02). The data support the concept that the murine "Z" gene is a potential model for the study of α(1)ATD and that mice expressing this gene would be relevant for testing treatments in vivo.

Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency.

BACKGROUND: The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency. METHODS: The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD. RESULTS: Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed. CONCLUSIONS: IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.

Management of radial artery perforation during coronary angiography and angioplasty--a report of two cases.

Perforation and disruption of the artery used for access is a recognized complication of coronary angiography. There is an increasing trend toward use of the radial artery for angiography and angioplasty, particularly in the primary angioplasty setting, because of the reduced risk of hemorrhagic complications. On the rare occasions when radial artery perforation occurs, operators have had a tendency to switch to a second arterial access route. This article describes a technique for managing peri-procedural perforation which does not require use of a second artery for access. We show two cases where this technique was used successfully, demonstrating an angiographically normal radial artery at the end of the procedure.

Use of a single Q guide catheter for complete assessment and treatment of both coronary arteries via radial access during acute ST elevation myocardial infarction: a review of 40 consecutive cases.

BACKGROUND: It is normally necessary to use more than 1 coronary catheter in primary percutaneous coronary intervention (PPCI) for ST elevation myocardial infarction (STEMI). We explored the utility of a single guide catheter (Q) strategy for complete coronary assessment and treatment in PPCI. METHODS: Fifty-seven consecutive STEMI cases undergoing invasive management were included. Radial access was the default route (6 cases via femoral access). Among radial cases, a TIG catheter was used first on 6 occasions (perceived low likelihood of subsequent PCI) and a Judkins right followed by an EBU catheter on three occasions (stock issue). A Q guide was used as initial default in the remaining 42 cases. Two anterior STEMI cases had recently undergone angiography and did not require right coronary reinspection. Procedural and outcomes data were recorded prospectively. RESULTS: The Q catheter allowed complete assessment and treatment in 33 cases, 6 cases requiring a second catheter and one patient dying prior to right coronary imaging. Territories of infarction were: anterior (n = 18), inferior (n = 14), inferoposterior (n = 3), lateral (n = 1), inferolateral (n = 2), inferoposterolateral (n = 2). Sixty-three out of 65 lesions were treated successfully. Median catheterization laboratory door to balloon time was 18 minutes (IQR 15-21 minutes). There were no catheter-related complications. CONCLUSIONS: A default Q guide catheter allows rapid effective imaging and treatment of both left and right coronaries in the majority of STEMI cases suitable for radial access PPCI.

Tumor necrosis factor-{alpha} rs361525 polymorphism is associated with increased local production and downstream inflammation in chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) has a genetic component, explaining susceptibility. Tumor necrosis factor (TNF)-alpha polymorphisms have been associated with COPD, but it is unclear if genotype influences clinical phenotype, protein expression, and bioactivity. OBJECTIVES: To determine if a functional polymorphism was important by assessing TNF-alpha expression and activity and its association with clinical severity over time. METHODS: Patients with COPD with rs361525 polymorphism were matched to patients with COPD without rs361525 polymorphism. TNF-alpha, its antagonists, and downstream mediators were measured in plasma and sputum. To determine TNF-alpha bioactivity, IL-8 secretion from primary bronchial epithelial cells (PBECs) was measured, and neutrophil migration was assessed using sputum from both subject groups in the presence and absence of TNF-alpha antibody. Subjects were followed annually and compared. MEASUREMENTS AND MAIN RESULTS: Patients with polymorphism had more chronic bronchitis, a lower body mass index, and a greater annual decline in FEV(1) than patients with COPD without rs361525 polymorphism. TNF-alpha concentrations were 100-fold higher in airway secretions from the patients with the rs361525 polymorphism, with no difference in TNF-alpha antagonists. Their lung secretions contained more IL-8 and myeloperoxidase, consistent with downstream inflammation. Sputum from patients with rs361525 polymorphism induced greater secretion of IL-8 from PBECs and increased neutrophil migration. These effects could be abrogated by TNF-alpha antibody, demonstrating the bioactivity of TNF-alpha in lung secretions from this group. CONCLUSIONS: This TNF-alpha polymorphism is associated with clinical features of disease including progression. There is clear evidence of TNF-alpha overexpression and bioactivity with neutrophilic inflammation. The polymorphism is likely to be a factor that influences a COPD disease phenotype and its progression.

Association between dose of catecholamines and markers of organ injury early after out-of-hospital cardiac arrest.

BACKGROUND: Catecholamines are recommended as first-line drugs to treat hemodynamic instability after out-of-hospital cardiac arrest (OHCA). The benefit-to-risk ratio of catecholamines is dose dependent, however, their effect on metabolism and organ function early after OHCA has not been investigated. METHODS: The Post-Cardiac Arrest Syndrome (PCAS) pilot study was a prospective, observational, multicenter study. The primary outcomes of this analysis were association between norepinephrine/cumulative catecholamines doses and neuron specific enolase (NSE)/lactate concentration over the first 72 hours after resuscitation. The association was adjusted for proven OHCA mortality predictors and verified with propensity score matching (PSM). RESULTS: Overall 148 consecutive OHCA patients; aged 18-91 (62.9 ± 15.27), 41 (27.7%) being female, were included. Increasing norepinephrine and cumulative catecholamines doses were significantly associated with higher NSE concentration on admission (r = 0.477, p < 0.001; r = 0.418, p < 0.001) and at 24 hours after OHCA (r = 0.339, p < 0.01; r = 0.441, p < 0.001) as well as with higher lactate concentration on admission (r = 0.404, p < 0.001; r = 0.280, p < 0.01), at 24 hours (r = 0.476, p < 0.00; r = 0.487, p < 0.001) and 48 hours (r = 0.433, p < 0.01; r = 0.318, p = 0.01) after OHCA. The associations remained significant up to 48 hours in non-survivors after PSM. CONCLUSIONS: Increasing the dose of catecholamines is associated with higher lactate and NSE concentration, which may suggest their importance for tissue oxygen delivery, anaerobic metabolism, and organ function early after OHCA.

Risks and benefits of percutaneous coronary intervention in spontaneous coronary artery dissection.

OBJECTIVE: To investigate percutaneous coronary intervention (PCI) practice in an international cohort of patients with spontaneous coronary artery dissection (SCAD). To explore factors associated with complications and study angiographic and longer term outcomes. METHODS: SCAD patients (n=215, 94% female) who underwent PCI from three national cohort studies were investigated and compared with a matched cohort of conservatively managed SCAD patients (n=221). RESULTS: SCAD-PCI patients were high risk at presentation with only 8.8% undergoing PCI outside the context of ST-elevation myocardial infarction/cardiac arrest, thrombolysis in myocardial infarction (TIMI) 0/1 flow or proximal dissections. PCI complications occurred in 38.6% (83/215), with 13.0% (28/215) serious complications. PCI-related complications were associated with more extensive dissections (multiple vs single American Heart Association coronary segments, OR 1.9 (95% CI: 1.06-3.39),p=0.030), more proximal dissections (proximal diameter per mm, OR 2.25 (1.38-3.67), p=0.001) and dissections with no contrast penetration of the false lumen (Yip-Saw 2 versus 1, OR 2.89 (1.12-7.43), p=0.028). SCAD-PCI involved long lengths of stent (median 46mm, IQR: 29-61mm). Despite these risks, SCAD-PCI led to angiographic improvements in those with reduced TIMI flow in 84.3% (118/140). Worsening TIMI flow was only seen in 7.0% (15/215) of SCAD-PCI patients. Post-PCI major adverse cardiovascular and cerebrovascular events (MACCE) and left ventricular function outcomes were favourable. CONCLUSION: While a conservative approach to revascularisation is favoured, SCAD cases with higher risk presentations may require PCI. SCAD-PCI is associated with longer stent lengths and a higher risk of complications but leads to overall improvements in coronary flow and good medium-term outcomes in patients.

Women leaders in Cardiology. Contemporary profile of the WHO European region.

Aims: Women's participation is steadily growing in medical schools, but they are still not sufficiently represented in cardiology, particularly in cardiology leadership positions. We present the contemporary distribution of women leaders in cardiology departments in the World Health Organization European region. Methods and results: Between August and December 2020, we applied purposive sampling to collect data and analyse gender distribution of heads of cardiology department in university/third level hospitals in 23 countries: Austria, Azerbaijan, Belgium, Bosnia-Herzegovina, Croatia, France, Germany, Greece, Italy, North Macedonia, Morocco, Poland, Portugal, Russia, Serbia, Slovakia, Slovenia, Spain, Switzerland, Tunisia, Turkey, Ukraine, and the UK. Age, cardiology subspecialty, and number of scientific publications were recorded for a subgroup of cardiology leaders for whom data were available. A total of 849 cardiology departments were analysed. Women leaders were only 30% (254/849) and were younger than their men counterpart (♀ 52.2 ± 7.7 years old vs. ♂ 58.1 ± 7.6 years old, P = 0.00001). Most women leaders were non-interventional experts (♀ 82% vs. ♂ 46%, P < 0.00001) and had significantly fewer scientific publications than men {♀ 16 [interquartile range (IQR) 2-41] publications vs. ♂ 44 (IQR 9-175) publications, P < 0.00001}. Conclusion: Across the World Health Organization European region, there is a significant gender disparity in cardiology leadership positions. Fostering a diverse and inclusive workplace is a priority to achieve the full potential and leverage the full talents of both women and men.

Outdoor air pollution is associated with rapid decline of lung function in alpha-1-antitrypsin deficiency.

INTRODUCTION: Outdoor air pollutants are associated with respiratory morbidity and mortality, but little longitudinal work has been undertaken in this area in chronic obstructive pulmonary disease (COPD). Patients with alpha-1-antitrypsin deficiency (AATD) typically exhibit faster decline of lung function than subjects with usual COPD and thus represent a group in whom studies of factors influencing decline may be more easily clarified. METHODS: Decline of FEV(1) and KCO in subjects of the PiZZ genotype from the UK AATD registry were studied. Pollution levels (PM(10), ozone, sulphur dioxide, nitrogen dioxide) during the exposure window were extracted from GIS maps, matching the measurement to each patient's home address. Clinical predictors of decline were sought using generalised estimating equations, and pollutants added to these subsequently. Single pollutant models were used due to multicollinearity. RESULTS: In the FEV(1) decline analysis, higher baseline FEV(1) was associated with rapid decline of FEV(1) (p<0.001). High PM(10) exposure predicted more rapid decline of FEV(1) (p=0.024). In a similar analysis for KCO decline, higher baseline KCO predicted rapid decline (p<0.001) as did higher exposure to ozone (p=0.018). High PM(10) exposure also showed a trend towards this effect (p=0.056). CONCLUSIONS: Exposure to ozone and PM(10) predicts decline of lung function in AATD.

Acute respiratory failure and inflammatory response after out-of-hospital cardiac arrest: results of the Post-Cardiac Arrest Syndrome (PCAS) pilot study.

BACKGROUND: Although the lungs are potentially highly susceptible to post-cardiac arrest syndrome injury, the issue of acute respiratory failure after out-of-hospital cardiac arrest has not been investigated. The objectives of this analysis were to determine the prevalence of acute respiratory failure after out-of-hospital cardiac arrest, its association with post-cardiac arrest syndrome inflammatory response and to clarify its importance for early mortality. METHODS: The Post-Cardiac Arrest Syndrome (PCAS) pilot study was a prospective, observational, six-centre project (Poland 2, Denmark 1, Spain 1, Italy 1, UK 1), studying patients resuscitated after out-of-hospital cardiac arrest of cardiac origin. Primary outcomes were: (a) the profile of organ failure within the first 72 hours after out-of-hospital cardiac arrest; (b) in-hospital and short-term mortality, up to 30 days of follow-up. Respiratory failure was defined using a modified version of the Berlin acute respiratory distress syndrome definition. Inflammatory response was defined using leukocytes (white blood cells), platelet count and C-reactive protein concentration. All parameters were assessed every 24 hours, from admission until 72 hours of stay. RESULTS: Overall, 148 patients (age 62.9±15.27 years; 27.7% women) were included. Acute respiratory failure was noted in between 50 (33.8%) and 75 (50.7%) patients over the first 72 hours. In-hospital and short-term mortality was 68 (46.9%) and 72 (48.6%), respectively. Inflammation was significantly associated with the risk of acute respiratory failure, with the highest cumulative odds ratio of 748 at 72 hours (C-reactive protein 1.035 (1.001-1.070); 0.043, white blood cells 1.086 (1.039-1.136); 0.001, platelets 1.004 (1.001-1.007); <0.005). Early acute respiratory failure was related to in-hospital mortality (3.172, 95% confidence interval 1.496-6.725; 0.002) and to short-term mortality (3.335 (1.815-6.129); 0.0001). CONCLUSIONS: An inflammatory response is significantly associated with acute respiratory failure early after out-of-hospital cardiac arrest. Acute respiratory failure is associated with a worse early prognosis after out-of-hospital cardiac arrest.

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene sets that have a significant enrichment of rare variants. METHODS: We sequenced a cohort of 384 SCAD survivors from the United Kingdom, alongside 13 722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants and exome-wide and gene-set rare variant collapsing analyses. RESULTS: The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the 2 cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in 7 genes (PKD1, COL3A1, SMAD3, TGFB2, LOX, MYLK, and YY1AP1) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, PKD1 was the highest-ranked gene, and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function. CONCLUSIONS: By studying the largest sequenced cohort of SCAD survivors, we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders, and we highlight several new genes for future validation.

Spontaneous Coronary Artery Dissection: Pathophysiological Insights From Optical Coherence Tomography.

OBJECTIVES: This study used optical coherence tomography to investigate the mechanism of false lumen (FL) formation in spontaneous coronary artery dissection (SCAD) by studying: 1) differences between fenestrated and nonfenestrated SCAD; 2) vasa vasorum density; and 3) light attenuation characteristics of the FL. BACKGROUND: SCAD is an increasingly recognized cause of acute coronary syndromes, characterized by FL formation and compression of the true lumen (TL). The mechanisms underlying FL formation remain poorly understood. METHODS: A total of 65 SCAD patients (68 vessels) who underwent acute OCT imaging as part of routine clinical care were included. Images were classified by the absence or presence of a connection (fenestration) between the TL and FL. Indexed measurements of TL stenosis, external elastic lamina (EEL) area, FL area, and light attenuation of the FL were assessed. Vasa vasorum densities of SCAD cases were compared with those in control non-SCAD myocardial infarction cases. RESULTS: In nonfenestrated cases, there was significantly larger expansion of the EEL area (9.1% vs. -1.9%; p <0.05) and a larger FL area (73.6% vs. 53.2%, respectively; p <0.05) in dissected segments. No significant differences were found between vasa vasorum density in SCAD and those in control subjects. The FL contents were heterogeneous but attenuated less light than whole blood or thrombus (4.28 ± 0.55 mm-1 vs. 5.08 ± 0.56 mm-1; p < 0.05; vs. 4.96 ± 0.56 mm-1; p < 0.05). CONCLUSIONS: These observational data suggest that the absence of a fenestration leads to increased FL pressure and compression of the TL. Although vasa vasorum may still be implicated in pathogenesis, increased vasa vasorum density could be an epiphenomenon of vascular healing.

Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. OBJECTIVES: This study sought to test the association between the rs9349379 genotype and SCAD. METHODS: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. RESULTS: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. CONCLUSIONS: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.