Objective:Excessive accumulation of resident cells within the pulmonary vascular wall represents the hallmark feature of the remodeling occurring in pulmonary arterial hypertension (PAH). Furthermore, we have previously demonstrated that pulmonary arterioles are excessively covered by pericytes in PAH, but this process is not fully understood. The aim of our study was to investigate the dynamic contribution of pericytes in PAH vascular remodeling.Approach and Results:In this study, we performed in situ, in vivo, and in vitro experiments. We isolated primary cultures of human pericytes from controls and PAH lung specimens then performed functional studies (cell migration, proliferation, and differentiation). In addition, to follow up pericyte number and fate, a genetic fate-mapping approach was used with an NG2CreER;mT/mG transgenic mice in a model of pulmonary arteriole muscularization occurring during chronic hypoxia. We identified phenotypic and functional abnormalities of PAH pericytes in vitro, as they overexpress CXCR (C-X-C motif chemokine receptor)-7 and TGF (transforming growth factor)-βRII and, thereby, display a higher capacity to migrate, proliferate, and differentiate into smooth muscle-like cells than controls. In an in vivo model of chronic hypoxia, we found an early increase in pericyte number in a CXCL (C-X-C motif chemokine)-12-dependent manner whereas later, from day 7, activation of the canonical TGF-β signaling pathway induces pericytes to differentiate into smooth muscle-like cells.Conclusions:Our findings reveal a pivotal role of pulmonary pericytes in PAH and identify CXCR-7 and TGF-βRII as 2 intrinsic abnormalities in these resident progenitor vascular cells that foster the onset and maintenance of PAH structural changes in blood lung vessels.

Objective:Pulmonary arterial hypertension (PAH) is a fatal disease characterized by the narrowing of pulmonary arteries (PAs). It is now established that this phenotype is associated with enhanced PA smooth muscle cells (PASMCs) proliferation and suppressed apoptosis. This phenotype is sustained in part by the activation of several DNA repair pathways allowing PASMCs to survive despite the unfavorable environmental conditions. PIM1 (Moloney murine leukemia provirus integration site) is an oncoprotein upregulated in PAH and involved in many prosurvival pathways, including DNA repair. The objective of this study was to demonstrate the implication of PIM1 in the DNA damage response and the beneficial effect of its inhibition by pharmacological inhibitors in human PAH-PASMCs and in rat PAH models.Approach and Results:We found in vitro that PIM1 inhibition by either SGI-1776, TP-3654, siRNA decreased the phosphorylation of its newly identified direct target KU70 (lupus Ku autoantigen protein p70) resulting in the inhibition of double-strand break repair (Comet Assay) by the nonhomologous end-joining as well as reduction of PAH-PASMCs proliferation (Ki67-positive cells) and resistance to apoptosis (Annexin V positive cells) of PAH-PASMCs. In vivo, SGI-1776 and TP-3654 given 3× a week, improved significantly pulmonary hemodynamics (right heart catheterization) and vascular remodeling (Elastica van Gieson) in monocrotaline and Fawn-Hooded rat models of PAH.Conclusions:We demonstrated that PIM1 phosphorylates KU70 and initiates DNA repair signaling in PAH-PASMCs and that PIM1 inhibitors represent a therapeutic option for patients with PAH.

Objective:The αIIbβ3 antagonist antiplatelet drug abciximab is the chimeric antigen-binding fragment comprising the variable regions of murine monoclonal antibody 7E3 and the constant domains of human IgG1 and light chain κ. Previous mutagenesis studies suggested that abciximab binds to the β3 C177-C184 specificity-determining loop (SDL) and Trp129 on the adjacent β1-α1 helix. These studies could not, however, assess whether 7E3 or abciximab prevents fibrinogen binding by steric interference, disruption of either the αIIbβ3-binding pocket for fibrinogen or the β3 SDL (which is not part of the binding pocket but affects fibrinogen binding), or some combination of these effects. To address this gap, we used cryo-electron microscopy to determine the structure of the αIIbβ3-abciximab complex at 2.8 Å resolution.Approach and Results:The interacting surface of abciximab is comprised of residues from all 3 complementarity-determining regions of both the light and heavy chains, with high representation of aromatic residues. Binding is primarily to the β3 SDL and neighboring residues, the β1-α1 helix, and β3 residues Ser211, Val212 and Met335. Unexpectedly, the structure also indicated several interactions with αIIb. As judged by the cryo-electron microscopy model, molecular-dynamics simulations, and mutagenesis, the binding of abciximab does not appear to rely on the interaction with the αIIb residues and does not result in disruption of the fibrinogen-binding pocket; it does, however, compress and reduce the flexibility of the SDL.Conclusions:We deduce that abciximab prevents ligand binding by steric interference, with a potential contribution via displacement of the SDL and limitation of the flexibility of the SDL residues.

Objective:Menopause may augment age-dependent increases in arterial stiffness, with black women having greater progression in midlife compared with white women. We sought to determine whether and when women experience changes in arterial stiffness relative to the final menstrual period (FMP) and whether these changes differ between black and white midlife women.Approach and Results:We evaluated 339 participants from the SWAN Heart Ancillary study (Study of Women’s Health Across the Nation). Women had ≤2 carotid-femoral pulse-wave velocity (cfPWV) exams over a mean±SD of 2.3±0.5 years of follow-up. Annual percentage changes in cfPWV were estimated in 3 time segments relative to FMP and compared using piecewise linear mixed-effects models. At baseline, women were 51.1±2.8 years of age and 36% black. Annual percentage change (95% CI) in cfPWV varied by time segments: 0.9% (−0.6% to 2.3%) for >1 year before FMP, 7.5% (4.1%–11.1%) within 1 year of FMP, and −1.0% (−2.8% to 0.8%) for >1 year after FMP. Annual percentage change in cfPWV within 1 year of FMP was significantly greater than the other 2 time segments; P<0.05 for both comparisons. Adjusting for concurrent cardiovascular disease risk factors explained part of the change estimates but did not eliminate the difference. Black women had greater increase in cfPWV compared with white women in the first segment; P for interaction, 0.04.Conclusions:The interval within 1 year of FMP is a critical period for women when vascular functional alterations occur. These findings underscore the importance of more intensive lifestyle modifications in women transitioning through menopause.

Objective:To determine the spectrum of phenotypes linked to the ABO blood group system, using genetic determinants of the ABO blood group system.Approach and Results:We assessed the risk of 41 health and disease outcomes, and 36 linear traits associated with the ABO blood group system in the UK Biobank cohort. A total of 406 755 unrelated individuals were included in this study. Blood groups A, B, and O were determined based on allele combinations of previously established single-nucleotide polymorphisms rs8176746, rs8176719 in the ABO gene. Group AB was excluded because of its relative small sample size. Overall, 187 387 (46%) were male with a mean (SD) age of 57±8.1 years and a median total exposure of 64 person-years (interquartile range, 57–70). Of 406 755 individuals, 182 621 (44.9%) participants had blood group O, 182 786 (44.9%) had blood group A, and 41 348 (10.2%) had blood group B. ABO blood groups were associated with 11 health and disease outcomes (P<2.19×10−4). ABO blood groups were primarily associated with cardiovascular outcomes. Compared with individuals with blood group O, blood groups A and B were associated with increased odds of up to 1.56 (95% CI, 1.43–1.69) for thromboembolic events and decreased odds for hypertension (0.94 [95% CI, 0.92–0.97]).Conclusions:The ABO blood group system is associated with several parameters of healthy aging and disease development. Knowledge of ABO blood groups might be of interest for more personalized approaches towards health maintenance and the prevention of diseases.

Androgen deprivation therapy is a central part of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, AR (androgen receptor) inhibition, and CYP17 inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.

Objectives This study investigated the prognostic utility of left ventricular (LV) untwisting (UT) in the elderly patients at risk of heart failure (HF). Background LV UT mechanics represent a unique combination of LV filling linking ventricular relaxation and suction. The value of this parameter in the prediction of outcomes in patients at risk of HF is unclear. Methods A group of 465 asymptomatic subjects ≥65 years of age with ≥1 HF risk factor (hypertension, diabetes, obesity), recruited from the community, underwent clinical evaluation and echocardiography including measurement of LV apical and basal peak UT velocities. Cox regression analysis was used to identify predictors of new-onset HF and cardiovascular death after a mean follow-up of 18.2 ± 7.5 months. Results A composite of both of the study endpoints occurred in 54 patients (11.6%). Adverse outcome was significantly associated with apical (hazard ratio [HR]: 0.98; 95% confidence interval [CI]: 0.96 to 0.99; p = 0.006) UT but not with basal (p = 0.18) UT. The prognostic value of apical UT was independent of and incremental to clinical data, as expressed by the ARIC (Atherosclerosis Risk In Communities) study risk score, left atrial volume index (LAVI), and LV global longitudinal strain (GLS). The addition of apical UT to the model including ARIC risk score, LAVI, and GLS was associated with a 41% improvement in reclassification (p = 0.006). Conclusions Echocardiographic assessment of apical UT provides incremental value in predicting adverse outcome in asymptomatic patients with HF risk factors. The inclusion of apical UT to the diagnostic algorithm may improve the prognostication process in this population.

More than 26 million people worldwide, predominantly the elderly, currently have heart failure (HF) [(1)][1], and the number is expected to grow as the population ages. Between 2015 and 2050, the proportion of the world's population older than 60 years of age will nearly double from 12% to 22% [(2

Objectives This study determined the effects of doxorubicin and/or trastuzumab on diastolic function and the relationship between diastolic function and systolic dysfunction. Background Doxorubicin and trastuzumab can result in left ventricular ejection fraction (LVEF) declines. However, the effects of these therapies on diastolic function remain incompletely defined. Methods In a rigorously phenotyped, longitudinal cohort study of 362 breast cancer participants treated with doxorubicin, doxorubicin followed by trastuzumab, or trastuzumab alone, changes in diastolic function were evaluated using linear models estimated via generalized estimating equations. Associations between baseline and changes in diastolic function with LVEF and longitudinal strain were also determined using generalized estimating equations. The Kaplan-Meier estimator derived the proportion of participants who experienced incident diastolic dysfunction. Cox proportional hazards models estimated the associations between participant characteristics and diastolic dysfunction risk, and between diastolic function and cancer therapy−related cardiac dysfunction risk, defined by an LVEF decline of ≥10% to <50%. Results Over a median of 2.1 years (interquartile range [IQR]: 1.3 to 4.2 years), participants treated with doxorubicin or doxorubicin followed by trastuzumab demonstrated a persistent worsening in diastolic function, with reductions in the E/A ratio, lateral and septal e′ velocities, and increases in E/e′ (p < 0.01). These changes were not observed with trastuzumab alone. Incident abnormal diastolic function grade occurred in 60% at 1 year, 70% by 2 years, and 80% by 3 years. Abnormal diastolic function grade was associated with a subsequent decrease in LVEF (−2.1%; 95% confidence intervals [CI]: −3.1 to −1.2; p < 0.001) and worsening in longitudinal strain (0.6%; 95% CI: 0.1 to 1.1; p = 0.013) over time. Changes in E/e′ ratio were modestly associated with worsening longitudinal strain (0.1%; 95% CI: 0.0 to 0.2; p = 0.022). Conclusions A modest, persistent worsening of diastolic function is observed with contemporary breast cancer therapy. Abnormal and worsening diastolic dysfunction is associated with a small risk of subsequent systolic dysfunction. (Cardiotoxicity of Cancer Therapy [CCT]; [NCT01173341][1]) [1]: https://clinicaltrials.gov/ct2/show/NCT01173341

Cancer therapeutics-related cardiac dysfunction (CTRCD) is commonly defined by a threshold change in left ventricular ejection fraction (LVEF) [(1)][1]. Although assessment of diastolic parameters is also recommended in this population, the timing of diastolic dysfunction (DD) in relationship to

Asymptomatic left ventricular diastolic dysfunction (ALVDD) (diastolic abnormalities and normal ejection fraction in the absence of symptoms) is associated with incident heart failure (HF) and decreased survival. Abnormalities of diastolic function might therefore be included in the definition of stage B HF, which denotes individuals at risk for the development of HF. Imaging techniques, especially echocardiography, are necessary for the recognition of preclinical left ventricular (LV) diastolic disturbances, as well as further tracking of pathological changes and responses to treatment. The transition of ALVDD to symptomatic HF is underlain by multiple factors, including both cardiovascular and noncardiovascular determinants. The initiation of management strategies targeting cardiovascular and systemic comorbidities in patients identified as having ALVDD may delay symptomatic progression and improve prognosis.

Left ventricular diastolic function plays an important role in determining left ventricular filling and stroke volume. Abnormal diastolic function has been recognized in many cardiovascular diseases and is associated with worse outcomes, including total mortality and hospitalizations due to heart failure. Using echocardiography, it is possible to diagnose the presence of diastolic dysfunction and the pathophysiologic mechanisms involved as they affect left ventricular and left atrial structure and function. This review addresses the role of echocardiography in understanding the pathophysiology of diastolic dysfunction, its diagnosis, and utility in predicting outcomes.

Research in the last decade has substantially advanced our understanding of the pathophysiology of heart failure with preserved ejection fraction (HFpEF). However, treatment options remain limited as clinical trials have largely failed to identify effective therapies. Part of this failure may be related to mechanistic heterogeneity. It is speculated that categorizing HFpEF patients based upon underlying pathophysiological phenotypes may represent the key next step in delivering the right therapies to the right patients. Echocardiography may provide valuable insight into both the pathophysiology and underlying phenotypes in HFpEF. Echocardiography also plays a key role in the evaluation of patients with unexplained dyspnea, where HFpEF is suspected but the diagnosis remains unknown. The combination of the E/e′ ratio and right ventricular systolic pressure has recently been shown to add independent value to the diagnostic evaluation of patients suspected of having HFpEF. Finally, echocardiography enables identification of the different causes that mimic HFpEF but are treated differently, such as valvular heart disease, pericardial constriction, and high-output heart failure or infiltrative myopathies such as cardiac amyloid. This review summarizes the current understanding of the pathophysiology and phenotyping of HFpEF with particular attention to the role of echocardiography in this context.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical entity that is poorly understood yet present in up to 5.5% of the general population. Proven therapies for this disorder are lacking, even though it has a similar prognosis to that of heart failure with reduced ejection fraction (HFrEF). Innovative imaging techniques have provided in-depth understanding of the unique pattern of left ventricular mechanics in patients with HFpEF who progress through preclinical (Stages A to B) and clinical (Stages C to D) American College of Cardiology/American Heart Association heart failure stages. This review highlights the mechanical basis of this disorder from the cellular and myofiber level to chamber dysfunction. As each chamber of the heart is examined, specific biomarkers and echocardiographic parameters with diagnostic and prognostic values are discussed. Finally, novel phenotyping methods including machine learning are reviewed that integrate these mechanics into clinical groups to advise and treat patients.

Diastolic dysfunction is a key factor in the pathogenesis of heart failure. Around 50% of cases of heart failure, the hemodynamic correlate of which is increased left ventricular filling pressure, are caused by diastolic dysfunction in the setting of apparently normal systolic function. Due to its high prevalence, diastolic dysfunction is often recognized as an incidental finding. Many patients have Doppler echocardiographic evidence of impaired diastolic function but do not have any symptoms of heart failure at rest. In many of these patients, symptoms of diastolic dysfunction occur only during exercise, as left ventricular filling pressure is normal at rest, but increases with exercise. This implies that filling pressures should also be measured during exercise. The diastolic stress test refers to the evaluation of diastolic function, either invasively or noninvasively, during exercise. This review focuses on the clinical need for diastolic stress testing, both invasively and noninvasively.

Heart failure with preserved ejection fraction presents a challenging diagnosis given a heterogeneous patient population and limited therapeutic options. Diastolic function assessment using echocardiography has been a cornerstone in the work-up and is as important as systolic functional assessment. There has been increased awareness to the potential utility of cardiac magnetic resonance (CMR) imaging over the past decade as a promising, radiation-free, robust imaging modality providing an unrestricted field of view and high-resolution images for global and regional functional assessment. CMR provides early markers for detecting myocardial disease using tissue characterization imaging, which might prove useful to improve diagnosis and management. Over the years, several studies have examined CMR-derived diastolic functional indices, including transmitral and pulmonary venous velocities, left ventricular and left atrial strain using myocardial tagging, and, more recently, feature tracking. The relevance of imaging-based diastolic function indices and their clinical application across different modalities is increasingly recognized.

Symptoms of heart failure (HF) are due in large part to elevation of left and/or right ventricular filling pressures. Although abnormal diastolic function is difficult to define, it contributes to the elevation of filling pressures. Tests that characterize aspects of diastolic function or structural changes associated with diastolic dysfunction, may help in establishing a diagnosis of HF, assessing prognosis, and guiding treatments. Individual echocardiographic parameters correlate weakly with LV (LV) filling pressures measured directly. However, a combination of multiple parameters improves accuracy for detection of elevated filling pressures. Serum natriuretic peptide levels are related to ventricular filling pressures and, when elevated, are a key diagnostic criterion for HF. Currently available evidence is not adequate to recommend serial echocardiographic studies or natriuretic peptide level measurements to assess changes in filling pressures or to guide HF therapy. Measurements of inferior vena cava size and dynamics have potential for identifying inadequate decongestion during episodes of acute decompensated HF but have not yet demonstrated utility in improving HF outcomes. Direct measurement of LV filling pressures using implanted pressure sensors is the only “diastolic assessment” thus far that has proven efficacy in reducing HF hospitalization rates.

By assessing nonhospitalized asymptomatic patients, community-based studies inform the prevalence, key clinical characteristics, and outcomes associated with diastolic dysfunction. As the number of parameters to define and grade diastolic function continues to increase, there has been a shift to a focus on readily obtainable measurements with minimal interobserver variability. In this regard, mitral inflow and annular tissue Doppler velocities, as well as measurement of left atrial volume index, are the most feasible and reproducible. Within communities, variations in definitions have limited generalizability regarding the prevalence and risks associated with diastolic dysfunction. Nevertheless, community-based studies have established important associations with hypertension, obesity, and diabetes. Randomized controlled trials of treatment in heart failure with preserved ejection fraction have been disappointing. Importantly, diastolic dysfunction is consistently associated with higher mortality, which emphasizes the importance of early recognition and initiation of appropriate preventative treatments.

Jae K. Oh, MD, William R. Miranda, MD, Jared G. Bird, MD, Garvan C. Kane, MD, PhD Determination of diastolic function is an integral part of an echocardiography examination, especially in patients with symptoms of heart failure. To standardize the evaluation of diastolic function, the American

We read with great interest the study by Lancaster et al. [(1)][1] regarding the use of a machine-learning algorithm for the unsupervised clustering of diastolic function variables. The authors reported improved prediction of clinical outcomes with machine learning over classification with the 2016

We thank Dr. Kampaktsis and colleagues for their interest in our investigation. Although we agree that the 2016 guidelines may have made diastolic dysfunction (DD) more conceptually simple in a clinical approach; there are 2 problems with this apparent simplification. First, the large number of

![Figure][1] “Everything should be made as simple as possible, but no simpler.”—Albert Einstein ![Figure][1] Left ventricular (LV) diastolic function determines LV filling and diastolic pressures. It is a complex process that depends on many factors, including LV end diastolic

This is a new variation of our educational iPix series — where important teaching points are conveyed through visually appealing multimedia. This new feature format is entirely case based — studies were obtained from real patients referred to the imaging laboratory seeking answers to important

Rationale: Heart failure (HF) following heart damage leads to a decreased blood flow due to a reduced pump efficiency of the heart muscle. A consequence can be insufficient oxygen supply to the organism including the brain. While HF clearly shows neurological symptoms, such as fatigue, nausea and dizziness, the implications for brain structure are not well understood. Few studies show regional gray matter decrease related to HF, however, the underlying mechanisms leading to the observed brain changes remain unclear.Objective: To study the relationship between impaired heart function, hampered blood circulation and structural brain change in a case-control study.Methods and Results: Within a group of 80 patients of the Leipzig Heart Center, we investigated a potential correlation between HF biomarkers and the brain's gray matter density (GMD) obtained by magnetic resonance imaging. We observed a significant positive correlation between cardiac ejection fraction and GMD across the whole frontal and parietal medial cortex reflecting the consequence of HF onto the brain's gray matter. Moreover, we also obtained a relationship between GMD and the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) − a biomarker that is used for screening, diagnosis and prognosis of HF. Here we found a significant negative correlation between NT-proBNP and GMD in the medial and posterior cingulate cortex but also in precuneus and hippocampus, which are key regions implicated in structural brain changes in dementia.Conclusions: We obtained significant correlations between brain structure and markers of heart failure including EF and NT-proBNP. A diminished GMD was found with decreased EF and increased NT-proBNP in wide brain regions including the whole frontomedian cortex as well as hippocampus and precuneus. Our observations might reflect structural brain damage in areas that are related to cognition, however, whether these structural changes facilitate the development of cognitive alterations has to be proven by further longitudinal studies.

In this review I try to summarize concisely available information on common effectors on blood pressure, occupational, and environmental ones, which are sometimes overlooked, so that clinicians involved in caring for patients with hypertension may have somewhat better vision of what our patients are exposed to.

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Background and Purpose—The benefit that endovascular thrombectomy offers to patients with stroke with large vessel occlusions depends strongly on reperfusion grade as defined by the expanded Thrombolysis in Cerebral Infarction (eTICI) scale. Our aim was to determine the lifetime health and cost consequences of the quality of reperfusion for patients, healthcare systems, and society.Methods—A Markov model estimated lifetime quality-adjusted life years (QALY) and lifetime costs of endovascular thrombectomy–treated patients with stroke based on eTICI grades. The analysis was performed over a lifetime horizon in a United States setting, adopting healthcare and societal perspectives. The reference case analysis was conducted for stroke at 65 years of age. National health and cost consequences of improved eTICI 2c/3 reperfusion rates were estimated. Input parameters were based on best available evidence.Results—Lifetime QALYs increased for every grade of improved reperfusion (median QALYs for eTICI 0/1: 2.62; eTICI 2a: 3.46; eTICI 2b: 5.42; eTICI 2c: 5.99; eTICI 3: 6.73). Achieving eTICI 3 over eTICI 2b reperfusion resulted on average in 1.31 incremental QALYs as well as healthcare and societal cost savings of $10 327 and $20 224 per patient. A 10% increase in the eTICI 2c/3 reperfusion rate of all annually endovascular thrombectomy–treated patients with stroke in the United States is estimated to yield additional 3656 QALYs and save $21.0 million and $36.8 million for the healthcare system and society, respectively.Conclusions—Improved reperfusion grants patients with stroke additional QALYs and leads to long-term cost savings. Procedural strategies to achieve complete reperfusion should be assessed for safety and feasibility, even when initial reperfusion seems to be adequate.

Background and Purpose—Patients with acute ischemic stroke who have large vessel occlusion benefit from direct transport to a comprehensive stroke center (CSC) capable of endovascular therapy. To avoid harm for patients without large vessel occlusion from delayed access to intravenous thrombolysis (IVT), it has been suggested to only redirect patients with high likelihood of large vessel occlusion for whom the additional delay to intravenous thrombolysis (IVT) caused by transport to the CSC is below a certain threshold. However, which threshold achieves the greatest clinical benefit is unknown.Methods—We used mathematical modeling to calculate additional-delay-to-IVT thresholds associated with the greatest reduction in disability-adjusted life years in abstracted 2-stroke center and multiple-stroke center scenarios. Model parameters were extracted from recent meta-analyses or large prospective cohort studies. Uncertainty was quantified in probabilistic and 2-way univariate sensitivity analyses.Results—Assuming ideal treatment time performance metrics, transport to the nearest CSC was the preferred strategy irrespective of additional delay-to-IVT when the transfer time between primary stroke center and CSC was <40 minutes (95% credible interval: 25–66 minutes); otherwise, the optimal additional delay-to-IVT-threshold ranged from 28 to 139 minutes. In multiple-stroke center scenarios, optimal additional-delay-to-IVT thresholds were 30 to 54 minutes in urban and 49 to 141 minutes in rural settings; use of optimal thresholds as compared with a 15 minute-threshold saved 0 to 0.11 and 0 to 0.37 disability-adjusted life years per triage case, respectively. Assuming slower treatment times at primary stroke centers and CSCs yielded longer permissible additional delays.Conclusions—Our results suggest that patients with acute ischemic stroke with suspected large vessel occlusion should be redirected to a CSC if the additional delay to IVT is <30 minutes in urban and 50 minutes in rural settings.

Background and Purpose—We aimed to compare outcomes of ischemic stroke patients with nonvalvular atrial fibrillation between earlier and later initiation of direct oral anticoagulants (DOACs) after stroke onset.Methods—From data for 1192 nonvalvular atrial fibrillation patients with acute ischemic stroke or transient ischemic attack in a prospective, multicenter, observational study, patients who started DOACs during acute hospitalization were included and divided into 2 groups according to a median day of DOAC initiation after onset. Outcomes included stroke or systemic embolism, major bleeding, and death at 3 months, as well as those at 2 years.Results—DOACs were initiated during acute hospitalization in 499 patients in median 4 (interquartile range, 2–7) days after onset. Thus, 223 patients (median age, 74 [interquartile range, 68–81] years; 78 women) were assigned to the early group (≤3 days) and 276 patients (median age, 75 [interquartile range, 69–82] years; 101 women) to the late (≥4 days) group. The early group had lower baseline National Institutes of Health Stroke Scale score and smaller infarcts than the late group. The rate at which DOAC administration persisted at 2 years was 85.2% overall, excluding patients who died or were lost to follow-up. Multivariable Cox shared frailty models showed comparable hazards between the groups at 2 years for stroke or systemic embolism (hazard ratio, 0.86 [95% CI, 0.47–1.57]), major bleeding (hazard ratio, 1.39 [95% CI, 0.42–4.60]), and death (hazard ratio, 0.61 [95% CI, 0.28–1.33]). Outcome risks at 3 months also did not significantly differ between the groups.Conclusions—Risks for events including stroke or systemic embolism, major bleeding, and death were comparable whether DOACs were started within 3 days or from 4 days or more after the onset of nonvalvular atrial fibrillation–associated ischemic stroke or transient ischemic attack.Registration—URL: https://www.clinicaltrials.gov. Unique identifier: NCT01581502.

Background and Purpose—Poststroke autonomic dysfunction portended an unfavorable prognosis. We investigated whether blood pressure variability (BPV), heart rate variability, and baroreflex sensitivity might predict stroke functional outcome.Methods—We calculated BPV, heart rate variability, baroreflex slope, and baroreflex effectiveness index from a 5-minute beat-to-beat blood pressure and heart rate monitoring within 7 days from the stroke onset. We compared the parameters between patients with a good outcome (modified Rankin Scale score, 0–2) and those with a poor outcome.Results—Among 142 patients (mean age, 63.9±10.2 years; 88.0% men), functional outcome was good in 112 (78.9%) and poor in 30 (21.1%). There were significant differences in admission National Institutes of Health Stroke Scale, prior stroke, high-frequency systolic BPV, low/high-frequency ratio of BPV, baroreflex sensitivity-up, and baroreflex sensitivity-total between the 2 groups (all P<0.05). In multivariate analysis, National Institutes of Health Stroke Scale (OR, 1.672 [95% CI, 1.316–2.125]; P<0.001), low/high-frequency ratio of systolic BPV (OR, 0.493 [95% CI, 0.250–0.973]; P=0.041), and baroreflex effectiveness index-down (OR, 0.958 [95% CI, 0.924–0.992]; P=0.017) independently predicted a poor functional outcome.Conclusions—A decreased low/high-frequency ratio of systolic BPV and impaired baroreflex sensitivity predicted an unfavorable stroke outcome, in addition to the established prognostic factor such as the National Institutes of Health Stroke Scale.

Background and Purpose—In acute spontaneous intracerebral hemorrhage, multiple hematoma expansion scores have been proposed for use in clinical trial environments. We performed a systematic scoping review to identify all existing hematoma expansion scores and describe their development, validation, and relative performance.Methods—Two reviewers searched MEDLINE, PUBMED, EMBASE, and CENTRAL (Cochrane Central Register of Controlled Trials) for studies that derived or validated a hematoma expansion prediction score in adults presenting with spontaneous intracerebral hemorrhage. A descriptive analysis of the extracted data was performed, focusing on score development techniques and predictive capabilities.Results—Of the 14 434 records retrieved, 15 studies met inclusion criteria and 10 prediction scores were identified. Validation analysis using independent samples was performed in 9 studies on 5 scores. All derivation studies reported high performance with C statistics ranging from 0.72 to 0.93. In validation, the C-statistic range was broader with studies reporting 0.62 to 0.77. For every score, the risk of expansion increased with each point increase, although patients with high scores were rare.Conclusions—At present, 10 hematoma expansion scores have been developed, of which 5 have been externally validated. Real-world performance in validation studies was lower than performance in derivation studies. Data from the current literature are insufficient to support a meaningful meta-analysis.

Background and Purpose—Fluoroquinolone use is associated with an increased risk of aortic aneurysm and dissection. We investigated this risk of arterial wall injury on intracranial arteries, given the similar pathophysiological mechanisms for aneurysm and dissection in both types of arteries.Methods—A case-time-control study was conducted using French National Insurance databases covering >60 million inhabitants. Cases were aged ≥18 years with first ruptured intracranial aneurysm and dissection between 2010 and 2015. For each case, fluoroquinolone use was compared between the exposure-risk window (day 30–day 1 before the outcome) and matched control windows (day 120–day 91, day 150–day 121, and day 180–day 151) and adjusted for time-varying confounders; potential time-trend for exposure was controlled using an age- and sex-matched reference group. Amoxicillin use was studied similarly for indication bias controlling. The potential excess of risk conveyed by fluoroquinolones was assessed by the ratio of OR for fluoroquinolones to that for amoxicillin.Results—Of the 7443 identified cases, 75 had been exposed to fluoroquinolones in the prior 180 days, including 16 in the 30-day at-risk window (385/97 cases exposed to amoxicillin, respectively). The adjusted OR for fluoroquinolones was 1.26 (95%CI, 0.65–2.41) and that for amoxicillin of 1.36 (95% CI, 1.05–1.78). Ratio of OR for fluoroquinolones to that for amoxicillin was estimated at 0.92 (95% CI, 0.46–1.86). Result was similar when extending outcome definition to unruptured events (ratio of OR for fluoroquinolones to that for amoxicillin, 0.97 [95% CI, 0.61–1.53]).Conclusions—This study did not evidence an excess of risk of intracranial aneurysm or dissection with fluoroquinolone use.

Background and Purpose—One-third of ruptured aneurysms are located on the anterior communicating complex with high prevalence of anatomic variations of this arterial segment. In this study, we hypothesized that anatomic variations of the anterior communicating complex increase the risk of angiographic vasospasm.Methods—Retrospective study of prospectively collected data from a monocentric subarachnoid hemorrhage cohort of patients admitted to neurointensive care between 2002 and 2018. Univariate followed by multivariate logistic regression analysis was used to identify factors associated with angiographic vasospasm.Results—One thousand three hundred seventy-four patients with aneurismal subarachnoid hemorrhage were admitted to our institution; 29.8% (n=410) were related to an anterior communicating complex aneurysm rupture; 9.2% (n=38) of them showed an anterior communicating artery variation. Angiographic vasospasm was diagnosed in 55.6% of this subgroup (vs 28.1%, P=0.003). In the multivariate analysis, external ventricular drain (2.2 [1.32–3.65], P=0.003) and anterior communicating artery variation (2.40 [1.2–4.9], P=0.04) were independently and significantly associated with angiographic vasospasm, while age above 60 years (0.3 [0.2–0.7]; P=0.002) was a protective factor. However, anterior communicating artery variation was not statistically associated with ischemic vasospasm or poor neurological outcome after anterior communicating artery aneurysm rupture.Conclusions—Anatomic variation of anterior communicating artery could be a new biomarker to identify patients at risk to develop angiographic vasospasm post-subarachnoid hemorrhage. External validation cohorts are necessary to confirm these results.

As transcatheter valves are offered to progressively lower-risk patients, it is increasingly important to have accurate data about durability. Structural valve deterioration (SVD) implies an adverse change in the morphology of the leaflets and function of the valve compared with the state at implantation. However, a recent European statement allows SVD to be defined solely by a threshold mean gradient ≥20 mm Hg. Absolute mean gradients above this threshold may be observed immediately after implantation and represent patient–prosthesis mismatch and not SVD. This paper describes a definition of SVD more in keeping with routine clinical practice, incorporating a change in leaflet morphology and an increase in the grade of transvalvar regurgitation or an increase in gradient from the post-implantation study.

In the evolving scenario of transcatheter aortic valve replacement (TAVR), the topic of bioprosthetic valve durability is becoming increasingly important. Unfortunately, the definition of long-term durability of surgical and transcatheter bioprostheses has been inconsistent over time. Comparative studies of TAVR and surgical aortic valve replacement, or studies comparing TAVR devices, would benefit from the use of standardized definitions of valve durability. The definitions of structural valve deterioration and bioprosthetic valve failure developed by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) have been endorsed by both the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) and embraced by many investigators worldwide. In this viewpoint, the authors discuss the strengths and limitations of such approach, which is intended to balance the need for accuracy and simplicity in reporting of long-term durability.