Stroke; A Journal Of Cerebral Circulation[JOURNAL]
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200 papers
Dog Ownership and Survival After a Major Cardiovascular Event: A Register-Based Prospective Study.
Mubanga M, Byberg L, Egenvall A … +2 more , Ingelsson E, Fall T
Circ Cardiovasc Qual Outcomes · 2019 Oct · PMID 31592725 · Publisher ↗
BACKGROUND: Dog ownership is associated with increased physical activity levels and increased social support, both of which could improve the outcome after a major cardiovascular event. Dog ownership may be particularly...
BACKGROUND: Dog ownership is associated with increased physical activity levels and increased social support, both of which could improve the outcome after a major cardiovascular event. Dog ownership may be particularly important in single-occupancy households where ownership provides substitutive companionship and motivation for physical activity. METHODS AND RESULTS: We used the Swedish National Patient Register to identify all patients aged 40 to 85 presenting with an acute myocardial infarction (n=181 696; 5.7% dog ownership) or ischemic stroke (n=154 617; 4.8% dog ownership) between January 1, 2001 and December 31, 2012. Individual information was linked across registers for cause of death, sociodemographic, and dog ownership data. We evaluated all-cause mortality and risk of recurrent hospitalization for the same cause until December 31, 2012. Models were adjusted for socioeconomic, health, and demographic factors at study inclusion such as age, marital status, the presence of children in the home, area of residence, and income, as well as all registered comorbidities and hospitalization for cardiovascular disease in the past 5 years. Dog owners had a lower risk of death after hospitalization for acute myocardial infarction during the full follow-up period of 804 137 person-years, with an adjusted hazard ratio (HR) of 0.67 (95% CI, 0.61 to 0.75) for those who lived alone, and HR of 0.85 (95% CI, 0.80 to 0.90) for those living with a partner or a child. Similarly, after an ischemic stroke, dog owners were at lower risk of death during the full follow-up of 638 219 person-years adjusted HR of 0.73 (95% CI, 0.66 to 0.80) for those who lived alone and HR of 0.88 (95% CI, 0.83 to 0.93) for those living with a partner or a child. We further found an association of dog ownership with reduced risk of hospitalization for recurrent myocardial infarction (HR, 0.93; 95% CI, 0.87 to 0.99). CONCLUSIONS: We found evidence of an association of dog ownership with a better outcome after a major cardiovascular event. Although our models are adjusted for many potential confounders, there are also unmeasured confounders such as smoking that prevent us from drawing conclusions regarding a possible causal effect.
Direct Assessment of Health Utilities Using the Standard Gamble Among Patients With Primary Intracerebral Hemorrhage.
Slaughter KB, Meyer EG, Bambhroliya AB … +13 more , Meeks JR, Ahmed W, Bowry R, Behrouz R, Mir O, Begley C, Tyson JE, Miller C, Warach S, Grotta JC, McCullough LD, Savitz SI, Vahidy FS
Circ Cardiovasc Qual Outcomes · 2019 Sep · PMID 31514521 · Publisher ↗
BACKGROUND: Standard gamble (SG) directly measures patients' valuation of their health state. We compare in-hospital and day-90 SG utilities (SGU) among intracerebral hemorrhage patients and report a 3-way association be...
BACKGROUND: Standard gamble (SG) directly measures patients' valuation of their health state. We compare in-hospital and day-90 SG utilities (SGU) among intracerebral hemorrhage patients and report a 3-way association between SGU, EuroQoL-5 dimension, and modified Rankin Scale at day 90. METHODS AND RESULTS: Patients with intracerebral hemorrhage underwent in-hospital and day-90 assessments for the modified Rankin Scale, EuroQoL-5 dimension, and SG. SG provides patients a choice between their current health state and a hypothetical treatment with varying chances of either perfect health or a painless death. Higher SGU (scale, 0-1) indicates lower risk tolerance and thus higher valuation of the current health state. Logistic regression was used to estimate the likelihood of low SGU (≤0.6), and Wilcoxon paired signed-rank test compared in-hospital and day-90 SGU. In-hospital and day-90 SG was obtained from 381 and 280 patients, respectively, including 236 paired observations. Median (interquartile range) in-hospital and day-90 SGUs were 0.85 (0.40-0.98) and 0.98 (0.75-1.00; <0.001). In-hospital SGUs were lower with advancing age (=0.007), higher National Institutes of Health Stroke Scale, and intracerebral hemorrhage scores (<0.001). Proxy-based assessments resulted in lower SGUs; median difference (95% CI), -0.2 (-0.33 to -0.07). After adjustment, higher National Institutes of Health Stroke Scale and proxy assessments were independently associated with lower SGU, along with an effect modification of age by race. Day-90 SGU and modified Rankin Scale were significantly correlated; however, SGUs were higher than the EuroQoL-5 dimension utilities at higher modified Rankin Scale levels. CONCLUSIONS: Divergence between directly (SGU) and indirectly (EuroQoL-5 dimension) assessed utilities at high levels of functional disability warrant careful prognostication of intracerebral hemorrhage outcomes and should be considered in designing early end-of-life care discussions with families and patients.
Intravenous Tissue Plasminogen Activator in Stroke Mimics.
Ali-Ahmed F, Federspiel JJ, Liang L … +11 more , Xu H, Sevilis T, Hernandez AF, Kosinski AS, Prvu Bettger J, Smith EE, Bhatt DL, Schwamm LH, Fonarow GC, Peterson ED, Xian Y
Circ Cardiovasc Qual Outcomes · 2019 Aug · PMID 31412730 · Full text
BACKGROUND: The necessity for rapid evaluation and treatment of acute ischemic stroke with intravenous tPA (tissue-type plasminogen activator) may increase the risk of administrating tPA to patients presenting with nonce...
BACKGROUND: The necessity for rapid evaluation and treatment of acute ischemic stroke with intravenous tPA (tissue-type plasminogen activator) may increase the risk of administrating tPA to patients presenting with noncerebrovascular conditions that closely resemble stroke (stroke mimics). However, there are limited data on thrombolysis safety in stroke mimics. METHODS AND RESULTS: Using data from the Get With The Guidelines-Stroke Registry, we identified 72 582 patients with suspected ischemic stroke treated with tPA from 485 US hospitals between January 2010 and December 2017. We documented the use of tPA in stroke mimics, defined as patients who present with stroke-like symptoms, but after workup are determined not to have suffered from a stroke or transient ischemic attack, and compared characteristics and outcomes in stroke mimics versus those with ischemic stroke. Overall, 3.5% of tPA treatments were given to stroke mimics. Among them, 38.2% had a final nonstroke diagnoses of migraine, functional disorder, seizure, and electrolyte or metabolic imbalance. Compared with tPA-treated true ischemic strokes, tPA-treated mimics were younger (median 54 versus 71 years), had a less severe National Institute of Health Stroke Scale (median 6 versus 8), and a lower prevalence of cardiovascular risk factors, except for a higher prevalence of prior stroke/transient ischemic attack (31.3% versus 26.1%, all P<0.001). The rate of symptomatic intracranial hemorrhage was lower in stroke mimics (0.4%) as compared with 3.5% in ischemic strokes (adjusted odds ratio, 0.29; 95% CI, 0.17-0.50). In-hospital mortality rate was significantly lower in stroke mimics (0.8% versus 6.2%, adjusted odds ratio, 0.31; 95% CI, 0.20-0.49). Patients with stroke mimics were more likely to be discharged to home (83.8% versus 49.3%, adjusted odds ratio, 2.97; 95% CI, 2.59-3.42) and to ambulate independently at discharge (78.6% versus 50.6%, adjusted odds ratio, 1.86; 95% CI, 1.61-2.14). CONCLUSIONS: In this large cohort of patients treated with tPA, relatively few patients who received tPA for presumed stroke were ultimately not diagnosed with a stroke or transient ischemic attack. The complication rates associated with tPA in stroke mimics were low. Despite the potential risk of administering tPA to stroke mimics, opportunity remains for continued improvement in the rapid and accurate diagnosis and treatment of ischemic stroke.
Secular Trends in Procedural Stroke or Death Risks of Stenting Versus Endarterectomy for Symptomatic Carotid Stenosis.
Müller MD, von Felten S, Algra A … +15 more , Becquemin JP, Bulbulia R, Calvet D, Eckstein HH, Fraedrich G, Halliday A, Hendrikse J, Howard G, Gregson J, Jansen O, Brown MM, Mas JL, Brott TG, Ringleb PA, Bonati LH
Circ Cardiovasc Interv · 2019 Aug · PMID 31378071 · Full text
BACKGROUND: Over the past decades, stroke risk associated with carotid disease has decreased, reflecting improvements in medical therapy and a more rigorous control of vascular risk factors. It is less clear whether the...
BACKGROUND: Over the past decades, stroke risk associated with carotid disease has decreased, reflecting improvements in medical therapy and a more rigorous control of vascular risk factors. It is less clear whether the procedural risk of carotid revascularization has declined over time. METHODS: We analyzed temporal changes in procedural risks among 4597 patients with symptomatic carotid stenosis treated with carotid artery stenting (n=2326) or carotid endarterectomy (n=2271) in 4 randomized trials between 2000 and 2008, using generalized linear mixed-effects models with a random intercept for each source trial. Models were additionally adjusted for age and other baseline characteristics predicting treatment risk. The primary outcome event was any procedural stroke or death, occurring during or within 30 days after revascularization. RESULTS: The procedural stroke or death risk decreased significantly over time in all patients (unadjusted odds ratio per year, 0.91; 95% CI, 0.85-0.97; P=0.006). This effect was driven by a decrease in the carotid endarterectomy group (unadjusted odds ratio per year, 0.82; 95% CI, 0.73-0.92; P=0.003), whereas no significant decrease was found after carotid artery stenting (unadjusted odds ratio, 0.96; 95% CI, 0.88-1.04; P=0.33). Carotid endarterectomy patients had a lower procedural stroke or death risk compared with carotid artery stenting patients, and the difference significantly increased over time (interaction P=0.031). After adjustment for baseline characteristics, the results remained essentially the same. CONCLUSIONS: The risk of stroke or death associated with carotid endarterectomy for symptomatic carotid stenosis decreased over an 8-year period, independent of clinical predictors of procedural risk. No corresponding reduction in procedural risk was seen in patients treated with stenting. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov; http://www.isrctn.com. Unique identifier: NCT00190398 (EVA-3S), NCT00004732 (CREST), ISRCTN57874028 (SPACE), and ISRCTN25337470 (ICSS).
Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls.
Traylor M, Anderson CD, Rutten-Jacobs LCA … +23 more , Falcone GJ, Comeau ME, Ay H, Sudlow CLM, Xu H, Mitchell BD, Cole JW, Rexrode K, Jimenez-Conde J, Schmidt R, Grewal RP, Sacco R, Ribases M, Rundek T, Rosand J, Dichgans M, Lee JM, Langefeld CD, Kittner SJ, Markus HS, Woo D, Malik R, NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC)
Circ Genom Precis Med · 2019 Jul · PMID 31306060 · Full text
BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains u...
BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.
Early Clinical Impact of Cerebral Embolic Protection in Patients Undergoing Transcatheter Aortic Valve Replacement.
Kroon HG, van der Werf HW, Hoeks SE … +11 more , van Gils L, van den Berge FR, El Faquir N, Rahhab Z, Daemen J, Poelman J, Schurer RAJ, van den Heuvel A, de Jaegere P, van der Harst P, Van Mieghem NM
Circ Cardiovasc Interv · 2019 Jun · PMID 31195822 · Publisher ↗
Background We aimed to compare the rate of neurological events in patients with or without cerebral embolic protection (CEP) during transcatheter aortic valve replacement (TAVR). Methods and Results Data on clinical end...
Background We aimed to compare the rate of neurological events in patients with or without cerebral embolic protection (CEP) during transcatheter aortic valve replacement (TAVR). Methods and Results Data on clinical end points including neurological events ≤30 days post-TAVR were collected for all patients who underwent transfemoral TAVR in 2 academic tertiary care institutions. Patients were matched through propensity scoring, which resulted in 333 pairs of patients with versus without CEP out of a total of 831 consecutive patients. The median age was 81 (76-85) years, and the median logistic EuroScore was 14% (9%-20%). The CEP group experienced less neurological events at 24 hours (1% versus 4%; P=0.035) and at 30 days (3% versus 7%; P=0.029). There were significantly more disabling strokes in unprotected patients at 30 days (1% versus 4%; P=0.039). CEP was associated with significantly fewer neurological events at 24 hours after TAVR (odds ratio, 0.20; 95% CI, 0.06-0.73; P=0.015) by multiple regression analysis, while age and valve type did not contribute significantly. Overall, 67% (2 of 3) in the CEP versus 83% (10 of 12) in the non-CEP cohort experienced neurological events in protected areas (ie, not dependent on the left vertebral artery). Conclusions The use of filter-based CEP during TAVR was associated with less neurological events, especially in CEP-protected brain territories.
Patient Characteristics Associated With Antianginal Medication Escalation and De-Escalation Following Chronic Total Occlusion Percutaneous Coronary Intervention.
Hirai T, Qintar M, Grantham JA … +10 more , Sapontis J, Cohen DJ, Lombardi W, Karmpaliotis D, Moses J, Nicholson WJ, Nugent K, Gosch KL, Spertus JA, Salisbury AC
Circ Cardiovasc Qual Outcomes · 2019 Jun · PMID 31185735 · Publisher ↗
Background Prior research has shown that providers may infrequently adjust antianginal medications (AAMs) following chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Patient characteristics associat...
Background Prior research has shown that providers may infrequently adjust antianginal medications (AAMs) following chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Patient characteristics associated with AAM titration and the variation in postprocedure AAM management after CTO PCI across hospitals have not been reported. We sought to determine the frequency and potential correlates of AAM escalation and de-escalation after CTO PCI. Methods and Results Using the 12-center OPEN CTO registry (Outcomes, Patient Health Status, and Efficiency iN Chronic Total Occlusion Hybrid Procedures), we assessed AAM use at baseline and 6 months after CTO PCI. Escalation was defined as any addition of a new class of AAM or dose increase, whereas de-escalation was defined as a reduction in the number of AAMs or dose reduction. Angina was assessed 6 months after the index CTO PCI attempt using the Seattle Angina Questionnaire Angina Frequency domain. Potential correlates of AAM escalation (vs no change) or de-escalation (vs no change) were evaluated using multivariable modified Poisson regression models. Adjusted variation across sites was evaluated using median rate ratios. AAMs were escalated in 158 (17.5%), de-escalated in 351 (39.0%), and were unchanged at 6-month follow-up in 392 (43.5%). Patient characteristics associated with escalation included lung disease, ongoing angina, and periprocedural major adverse cardiac and cerebral events (periprocedural myocardial infarction, stroke, death, emergent cardiac surgery, or clinically significant perforation), whereas de-escalation was more frequent among patients taking more AAMs, those treated with complete revascularization, and after treatment of non-CTO lesions at the time of the index procedure. There was minimal variation in either escalation (median rate ratio, 1.11; P=0.36) or de-escalation (median rate ratio, 1.10; P=0.20) compared to no change of AAMs across sites. Conclusions Escalation or de-escalation of AAMs was less common than continuation following CTO PCI, with little variation across sites. Further research is needed to identify patients who may benefit from AAM titration after CTO PCI and develop strategies to adjust these medications in follow-up. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02026466.
Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation.
Senchenkova EY, Ansari J, Becker F … +17 more , Vital SA, Al-Yafeai Z, Sparkenbaugh EM, Pawlinski R, Stokes KY, Carroll JL, Dragoi AM, Qin CX, Ritchie RH, Sun H, Cuellar-Saenz HH, Rubinstein MR, Han YW, Orr AW, Perretti M, Granger DN, Gavins FNE
Circulation · 2019 Jul · PMID 31154815 · Full text
BACKGROUND: Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis...
BACKGROUND: Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation. Their role as participants in the resolution of thromboinflammation is underappreciated; therefore we used pharmacological and genetic approaches, coupled with murine and clinical samples, to uncover key concepts underlying this role. METHODS: Middle cerebral artery occlusion with reperfusion was performed in wild-type or annexin A1 (AnxA1) knockout (AnxA1) mice. Fluorescence intravital microscopy was used to visualize cellular trafficking and to monitor light/dye-induced thrombosis. The mice were treated with vehicle, AnxA1 (3.3 mg/kg), WRW4 (1.8 mg/kg), or all 3, and the effect of AnxA1 was determined in vivo and in vitro. RESULTS: Intravital microscopy revealed heightened platelet adherence and aggregate formation post I/RI, which were further exacerbated in AnxA1 mice. AnxA1 administration regulated platelet function directly (eg, via reducing thromboxane B and modulating phosphatidylserine expression) to promote cerebral protection post-I/RI and act as an effective preventative strategy for stroke by reducing platelet activation, aggregate formation, and cerebral thrombosis, a prerequisite for ischemic stroke. To translate these findings into a clinical setting, we show that AnxA1 plasma levels are reduced in human and murine stroke and that AnxA1 is able to act on human platelets, suppressing classic thrombin-induced inside-out signaling events (eg, Akt activation, intracellular calcium release, and Ras-associated protein 1 [Rap1] expression) to decrease αβ activation without altering its surface expression. AnxA1 also selectively modifies cell surface determinants (eg, phosphatidylserine) to promote platelet phagocytosis by neutrophils, thereby driving active resolution. (n=5-13 mice/group or 7-10 humans/group.) Conclusions: AnxA1 affords protection by altering the platelet phenotype in cerebral I/RI from propathogenic to regulatory and reducing the propensity for platelets to aggregate and cause thrombosis by affecting integrin (αβ) activation, a previously unknown phenomenon. Thus, our data reveal a novel multifaceted role for AnxA1 to act both as a therapeutic and a prophylactic drug via its ability to promote endogenous proresolving, antithromboinflammatory circuits in cerebral I/RI. Collectively, these results further advance our knowledge and understanding in the field of platelet and resolution biology.
Associations Between Age at Arterial Switch Operation, Brain Growth, and Development in Infants With Transposition of the Great Arteries.
Lim JM, Porayette P, Marini D … +13 more , Chau V, Au-Young SH, Saini A, Ly LG, Blaser S, Shroff M, Branson HM, Sananes R, Hickey EJ, Gaynor JW, Van Arsdell G, Miller SP, Seed M
Circulation · 2019 Jun · PMID 31132861 · Publisher ↗
BACKGROUND: Brain injury, impaired brain growth, and long-term neurodevelopmental problems are common in children with transposition of the great arteries. We sought to identify clinical risk factors for brain injury and...
BACKGROUND: Brain injury, impaired brain growth, and long-term neurodevelopmental problems are common in children with transposition of the great arteries. We sought to identify clinical risk factors for brain injury and poor brain growth in infants with transposition of the great arteries undergoing the arterial switch operation, and to examine their relationship with neurodevelopmental outcome. METHODS: The brains of 45 infants with transposition of the great arteries undergoing surgical repair were imaged pre- and postoperatively using magnetic resonance imaging. Brain weight z scores were calculated based on brain volume and autopsy reference data. Brain injury scores were determined as previously described. Neurodevelopment was assessed at 18 months using the Bayley-III scores of infant development. The relationships between clinical variables, brain injury, perioperative brain growth, and 18-month Bayley-III scores were analyzed. RESULTS: On preoperative imaging, moderate or severe white matter injury was present in 10 of 45 patients, whereas stroke was seen in 4 of 45. A similar prevalence of injury was seen on postoperative imaging, and we were unable to identify any clinical risk factors for brain injury. Brain weight z scores decreased perioperatively in 35 of 45 patients. The presence of a ventricular septal defect ( P=0.009) and older age at surgery ( P=0.007) were associated with impaired perioperative brain growth. When patients were divided into those undergoing surgery during the first 2 weeks of life (32/45) versus those being repaired later (13/45), infants repaired later had significantly worse perioperative brain growth (late repair postoperative brain weight z = -1.0±0.90 versus early repair z = -0.33±0.64; P=0.008). Bayley-III testing scores fell within the normal range for all patients, although age at repair ( P=0.03) and days of open chest ( P=0.03) were associated with a lower composite language score, and length of stay was associated with a lower composite cognitive score ( P=0.02). CONCLUSIONS: Surgery beyond 2 weeks of age is associated with impaired brain growth and slower language development in infants with transposition of the great arteries cared for at our center. Although the mechanisms underlying this association are still unclear, extended periods of cyanosis and pulmonary overcirculation may adversely impact brain growth and subsequent neurodevelopment.
Effects of Arteriovenous Fistula Ligation on Cardiac Structure and Function in Kidney Transplant Recipients.
Rao NN, Stokes MB, Rajwani A … +12 more , Ullah S, Williams K, King D, Macaulay E, Russell CH, Olakkengil S, Carroll RP, Faull RJ, Teo KSL, McDonald SP, Worthley MI, Coates PT
Circulation · 2019 Jun · PMID 31045455 · Publisher ↗
BACKGROUND: Cardiovascular morbidity and mortality remain high in recipients of a kidney transplant. The persistence of a patent arteriovenous fistula (AVF) after transplantation may contribute to ongoing maladaptive car...
BACKGROUND: Cardiovascular morbidity and mortality remain high in recipients of a kidney transplant. The persistence of a patent arteriovenous fistula (AVF) after transplantation may contribute to ongoing maladaptive cardiovascular remodeling. The ability to reverse this maladaptive remodeling by ligation of this AVF is unknown. We conducted the first randomized controlled trial to evaluate the effect of AVF ligation on cardiac structure and function in stable kidney transplant recipients. METHODS: In this randomized controlled trial, kidney transplant recipients (>12 months after transplantation with stable graft function) were randomized to AVF ligation or no intervention. All participants underwent cardiac magnetic resonance imaging at baseline and at 6 months. The primary outcome was the change in left ventricular (LV) mass. Secondary outcomes included changes in LV volumes, left and right atrial areas, LV ejection fraction, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, cardiac output/index, brachial flows (ipsilateral to AVF), and pulmonary artery velocity. RESULTS: A total of 93 patients were screened, of whom 64 met the inclusion criteria and were randomized to the AVF ligation (n=33) or control (n=31) group. Fifty-four participants completed the study: 27 in the AVF ligation group and 27 in the control group. On the second cardiac magnetic resonance scan, a mean decrease of 22.1 g (95% CI, 15.0-29.1) was observed in LV mass in the AVF ligation group compared with a small increase of 1.2 g (95% CI, -4.8 to 7.2) in the control group ( P<0.001). Significant decreases in LV end-diastolic volumes, LV end-systolic volumes, cardiac output, cardiac index, atrial volumes, and NT-proBNP were also seen in the AVF closure group ( P<0.01). No significant changes were observed in LV ejection fraction ( P=0.93) and pulmonary artery velocity ( P=0.07). No significant complications were noted after AVF ligation. No changes in estimated glomerular filtration rate or systolic and diastolic blood pressures were observed between cardiac magnetic resonance scans. CONCLUSIONS: Elective ligation of patent AVF in adults with stable kidney transplant function resulted in clinically significant reduction of LV myocardial mass. CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry URL: https://www.anzctr.org.au . Unique Identifier: ACTRN12613001302741.
Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction.
Furtado RHM, Bonaca MP, Raz I … +16 more , Zelniker TA, Mosenzon O, Cahn A, Kuder J, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Nicolau JC, Gause-Nilsson IAM, Fredriksson M, Langkilde AM, Sabatine MS, Wiviott SD
Circulation · 2019 May · PMID 30882239 · Publisher ↗
BACKGROUND: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because...
BACKGROUND: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. METHODS: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. RESULTS: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65-1.00; P=0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). CONCLUSIONS: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.
N-Terminal Pro-B-Type Natriuretic Peptide Levels for Risk Prediction in Patients With Heart Failure and Preserved Ejection Fraction According to Atrial Fibrillation Status.
Kristensen SL, Mogensen UM, Jhund PS … +10 more , Rørth R, Anand IS, Carson PE, Desai AS, Pitt B, Pfeffer MA, Solomon SD, Zile MR, Køber L, McMurray JJV
Circ Heart Fail · 2019 Mar · PMID 30871349 · Publisher ↗
Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is useful in diagnosis and prognostication in heart failure (HF). We examined the relationship between NT-proBNP and outcomes in patients with HF and prese...
Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is useful in diagnosis and prognostication in heart failure (HF). We examined the relationship between NT-proBNP and outcomes in patients with HF and preserved ejection fraction, with and without atrial fibrillation (AF). Methods and Results Among 3835 HF with preserved ejection fraction patients enrolled in the I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function trial) or TOPCAT trial (Treatment of Preserved Cardiac Function in Heart Failure With an Aldosterone Antagonist), 719 (19%) patients had AF on their baseline ECG. Median (Q1-Q3) levels of NT-proBNP were 1286 pg/mL (778-2072) in those with AF and 288 pg/mL (122-704) in those without ( P<0.001). We analyzed patients using 4 NT-proBNP bands: <400, 400 to 999 (reference), 1000 to 1999, and ≥2000 pg/mL. The event rates for the primary composite outcome of cardiovascular death or HF hospitalization were higher in patients with AF versus patients without or those without without AF in the lowest NT-proBNP band (<400 pg/mL; 8.0 versus 3.2 per 100 patient-years), whereas for the higher bands the opposite was true (1000-1999 pg/mL; 11.4 versus 13.2 per 100 patient-years and ≥2000 pg/mL; 17.4 versus 25.6 per 100 patient-years). In adjusted analyses, higher NT-proBNP levels were less predictive of HF hospitalization than mortality in patients with AF compared with those without. Conclusions Event rates in HF with preserved ejection fraction patients without AF and with NT-proBNP <400 pg/mL are low. Among patients with NT-proBNP ≥400 pg/mL, the relationship between NT-proBNP and outcomes differs with lower absolute risk in patients who have AF compared with those who do not have AF. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00094302 and NCT00095238.
B-Type Natriuretic Peptides and Cardiac Troponins for Diagnosis and Risk-Stratification of Syncope.
du Fay de Lavallaz J, Badertscher P, Nestelberger T … +25 more , Zimmermann T, Miró Ò, Salgado E, Christ M, Geigy N, Cullen L, Than M, Javier Martin-Sanchez F, Di Somma S, Frank Peacock W, Morawiec B, Walter J, Twerenbold R, Puelacher C, Wussler D, Boeddinghaus J, Koechlin L, Strebel I, Keller DI, Lohrmann J, Michou E, Kühne M, Reichlin T, Mueller C, BASEL IX Investigators
Circulation · 2019 May · PMID 30798615 · Publisher ↗
BACKGROUND: The utility of BNP (B-type natriuretic peptide), NT-proBNP (N-terminal proBNP), and hs-cTn (high-sensitivity cardiac troponin) concentrations for diagnosis and risk-stratification of syncope is incompletely u...
BACKGROUND: The utility of BNP (B-type natriuretic peptide), NT-proBNP (N-terminal proBNP), and hs-cTn (high-sensitivity cardiac troponin) concentrations for diagnosis and risk-stratification of syncope is incompletely understood. METHODS: We evaluated the diagnostic and prognostic accuracy of BNP, NT-proBNP, hs-cTnT, and hs-cTnI concentrations, alone and against those of clinical assessments, in patients >45-years old presenting with syncope to the emergency department in a prospective diagnostic multicenter study. BNP, NT-proBNP, hs-cTnT and hs-cTnI concentrations were measured in a blinded fashion. Cardiac syncope, as adjudicated by 2 physicians based on all information available including cardiac work-up and 1-year follow-up, was the diagnostic end point. EGSYS (Evaluation of Guidelines in Syncope Study), a syncope-specific diagnostic score, served as the diagnostic comparator. Death and major adverse cardiac events at 30 and 720 days were the prognostic end points. Major adverse cardiac events were defined as death, cardiopulmonary resuscitation, life-threatening arrhythmia, implantation of pacemaker/implantable cardioverter defibrillator, acute myocardial infarction, pulmonary embolism, stroke/transient ischemic attack, intracranial bleeding, or valvular surgery. ROSE (Risk Stratification of Syncope in the Emergency Department), OESIL (Osservatorio Epidemiologico della Sincope nel Lazio), SFSR (San Fransisco Syncope Rule), and CSRS (Canadian Syncope Risk Score) served as the prognostic comparators. RESULTS: Among 1538 patients eligible for diagnostic assessment, cardiac syncope was the adjudicated diagnosis in 234 patients (15.2%). BNP, NT-proBNP, hs-cTnT, and hs-cTnI were significantly higher in cardiac syncope versus other causes (<0.01). The diagnostic accuracy for cardiac syncope, as quantified by the area under the curve, was 0.77 to 0.78 (95% CI, 0.74-0.81) for all 4 biomarkers, and superior to EGSYS (area under the curve, 0.68 [95%-CI 0.65-0.71], <0.001). Combining BNP/NT-proBNP with hs-cTnT/hs-cTnI further improved diagnostic accuracy to an area under the curve of 0.81 (<0.01). BNP, NT-proBNP, hs-cTnT, and hs-cTnI cut-offs, achieving predefined thresholds for sensitivity and specificity (95%), allowed for rule-in or rule-out of ≈30% of all patients. A total of 450 major adverse cardiac events occurred during follow-up. The prognostic accuracy of BNP, NT-proBNP, hs-cTnI, and hs-cTnT for major adverse cardiac events was moderate-to-good (area under the curve, 0.75-0.79), superior to ROSE, OESIL, and SFSR, and inferior to CSRS. CONCLUSIONS: BNP, NT-proBNP, hs-cTnT, and hs-cTnI concentrations provide useful diagnostic and prognostic information in emergency department patients with syncope. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT01548352.
Sex-Related Differences in Patients Undergoing Thoracic Aortic Surgery.
Chung J, Stevens LM, Ouzounian M … +16 more , El-Hamamsy I, Bouhout I, Dagenais F, Cartier A, Peterson MD, Boodhwani M, Guo M, Bozinovski J, Yamashita MH, Lodewyks C, Atoui R, Bittira B, Payne D, Tarola C, Chu MWA, Canadian Thoracic Aortic Collaborative
Circulation · 2019 Feb · PMID 30755026 · Publisher ↗
BACKGROUND: Contemporary outcomes after surgical management of thoracic aortic disease have improved; however, the impact of sex-related differences is poorly understood. METHODS: A total of 1653 patients (498 [30.1%] fe...
BACKGROUND: Contemporary outcomes after surgical management of thoracic aortic disease have improved; however, the impact of sex-related differences is poorly understood. METHODS: A total of 1653 patients (498 [30.1%] female) underwent thoracic aortic surgery with hypothermic circulatory arrest between 2002 and 2017 in 10 institutions of the Canadian Thoracic Aortic Collaborative. Outcomes of interest were in-hospital death, stroke, and a modified Society of Thoracic Surgeons-defined composite for mortality or major morbidity (stroke, renal failure, deep sternal wound infection, reoperation, prolonged ventilation). Multivariable logistic regression was used to determine independent predictors of these outcomes. RESULTS: Women were older (mean±SD, 66±13 years versus 61±13 years; P<0.001), with more hypertension and renal failure, but had less coronary disease, less previous cardiac surgery, and higher ejection fraction than men. Rates of aortic dissection were similar between women and men. Rates of hemiarch, and total arch repair were similar between the sexes; however, women underwent less aortic root reconstruction including aortic root replacement, Ross, or valve-sparing root operations (29% versus 45%; P<0.001). Men experienced longer cross-clamp and cardiopulmonary bypass times, but similar durations of circulatory arrest, methods of cerebral perfusion, and nadir temperatures. Women experienced a higher rate of mortality (11% versus 7.4%; P=0.02), stroke (8.8% versus 5.5%; P=0.01), and Society of Thoracic Surgeons-defined composite end point for mortality or major morbidity (31% versus 27%; P=0.04). On multivariable analyses, female sex was an independent predictor of mortality (odds ratio, 1.81; P<0.001), stroke (odds ratio, 1.90; P<0.001), and Society of Thoracic Surgeons-defined composite end point for mortality or major morbidity (odds ratio, 1.40; P<0.001). CONCLUSIONS: Women experience worse outcomes after thoracic aortic surgery with hypothermic circulatory arrest. Further investigation is required to better delineate which measures may reduce sex-related outcome differences after complex aortic surgery.
Use, Temporal Trends, and Outcomes of Endovascular Therapy After Interhospital Transfer in the United States.
Shah S, Xian Y, Sheng S … +6 more , Zachrison KS, Saver JL, Sheth KN, Fonarow GC, Schwamm LH, Smith EE
Circulation · 2019 Mar · PMID 30700144 · Full text
BACKGROUND: The use of endovascular therapy (EVT) in patients with acute ischemic stroke who have large vessel occlusion has rapidly increased in the United States following pivotal trials demonstrating its benefit. Info...
BACKGROUND: The use of endovascular therapy (EVT) in patients with acute ischemic stroke who have large vessel occlusion has rapidly increased in the United States following pivotal trials demonstrating its benefit. Information about the contribution of interhospital transfer in improving access to EVT will help organize regional systems of stroke care. METHODS: We analyzed trends of transfer-in EVT from a cohort of 1 863 693 patients with ischemic stroke admitted to 2143 Get With The Guidelines-Stroke participating hospitals between January 2012 and December 2017. We further examined the association between arrival mode and in-hospital outcomes by using multivariable logistic regression models. RESULTS: Of the 37 260 patients who received EVT at 639 hospitals during the study period, 42.9% (15 975) arrived at the EVT-providing hospital after interhospital transfer. Transfer-in EVT cases increased from 256 in the first quarter 2012 to 1422 in the fourth quarter 2017, with sharply accelerated increases following the fourth quarter 2014 ( P<0.001 for change in linear trend). Transfer-in patients were younger and more likely to be of white race, to arrive during off-hours, and to be treated at comprehensive stroke centers. Transfer-in patients had significantly longer last-known-well-to-EVT initiation time (median, 289 minutes versus 213 minutes; absolute standardized difference, 67.33) but were more likely to have door-to-EVT initiation time of ≤90 minutes (65.6% versus 23.6%; absolute standardized difference, 93.18). In-hospital outcomes were worse for transfer-in patients undergoing EVT in unadjusted and in risk-adjusted models. Although the difference in in-hospital mortality disappeared after adjusting for delay in EVT initiation (14.7% versus 13.4%; adjusted odds ratio, 1.01; 95% CI, 0.92-1.11), transfer-in patients were still more likely to develop symptomatic intracranial hemorrhage (7.0% versus 5.7%; adjusted odds ratio, 1.15; 95% CI, 1.02-1.29) and less likely to have either independent ambulation at discharge (33.1% versus 37.1%; adjusted odds ratio, 0.87; 95% CI, 0.80-0.95) or to be discharged to home (24.3% versus 29.1%; adjusted odds ratio, 0.82; 95% CI, 0.76-0.88). CONCLUSIONS: Interhospital transfer for EVT is increasingly common and is associated with a significant delay in EVT initiation highlighting the need to develop more efficient stroke systems of care. Further evaluation to identify factors that impact EVT outcomes for transfer-in patients is warranted.
Impact of Participation in a Telestroke Network on Clinical Outcomes.
Zhang D, Shi L, Ido MS … +4 more , Green DE, Li Y, Su D, Hess DC
Circ Cardiovasc Qual Outcomes · 2019 Jan · PMID 30606053 · Publisher ↗
BACKGROUND: A telestroke program, known as the Remote Evaluation for Acute Ischemic Stroke program, has been implemented in Georgia since 2003. This study examined whether a hospital's participation in a telestroke netwo...
BACKGROUND: A telestroke program, known as the Remote Evaluation for Acute Ischemic Stroke program, has been implemented in Georgia since 2003. This study examined whether a hospital's participation in a telestroke network was associated with improvement in clinical outcomes and quality indicators. METHODS AND RESULTS: An observational study was conducted using data from the Georgia Coverdell Acute Stroke Registry between September 2005 and September 2016 for patients aged ≥18 years with ischemic stroke. We use a difference-in-differences approach to compare the following clinical outcomes and quality indicators among those admitted at hospitals within and outside of the Remote Evaluation for Acute Ischemic Stroke network: tPA (tissue-type plasminogen activator) use, complications related to tPA use, door-to-needle time, ambulation at discharge, discharge status, and destination. Logistic regression models and a propensity score weighting approach were performed to adjust for patients' age, sex, race, insurance coverage, arrival mode, ambulatory status before the current stroke, stroke severity, medical history, admission time, and hospital bed size. A total of 25 494 patients with ischemic stroke admitted at 15 nonteaching hospitals located outside of the Atlanta metropolitan area were included in the analysis. After propensity score weighting, hospitals participated in a telestroke network was not associated with a significant increase in the rate of tPA use, while it was significantly associated with a modest decline in the rate of complications related to tPA (-5.9%; 95% CI, -9.2% to -2.6%). Telestroke participation showed no significant difference in other clinical outcomes and quality measures except for a marginally significant decrease in in-hospital mortality (-1.1%; 95% CI, -2.2% to -0.1%). CONCLUSIONS: Although a slight decrease in tPA complication was observed among hospitals participating in the telestroke network, overall the impact of telestroke participation on a hospital's stroke care quality was not statistically significant based on our observational study.
Clinical Utility of Patient-Reported Outcome Measurement Information System Domain Scales.
Lapin B, Thompson NR, Schuster A … +1 more , Katzan IL
Circ Cardiovasc Qual Outcomes · 2019 Jan · PMID 30587028 · Publisher ↗
BACKGROUND: Patient-reported outcome measures are increasingly being utilized in clinical care and research to evaluate outcomes following stroke. To optimize the clinical utility of these measures, we aimed to quantify...
BACKGROUND: Patient-reported outcome measures are increasingly being utilized in clinical care and research to evaluate outcomes following stroke. To optimize the clinical utility of these measures, we aimed to quantify meaningful change by establishing minimal important differences (MIDs), or responder definitions, for 4 domains affected in ischemic and hemorrhagic stroke patients. METHODS AND RESULTS: We performed a retrospective cohort study of stroke patients seen in the Cleveland Clinic cerebrovascular center between September 2, 2012 and November 7, 2017. Four Patient-Reported Outcome Measurement Information System (PROMIS) scales were completed within 1 month poststroke and again at 6 months. MIDs were estimated using an anchor-based approach based on a global impression of change question and supported using 3 distribution-based methods. Cumulative distribution functions assessed responder thresholds. MIDs were additionally derived across sex, race, and varying levels of severity as defined by the modified Rankin Score and baseline PROMIS score. During the study period, 337 incident stroke patients completed at least 1 PROMIS domain scale at both time points (average age 61±14, 56% female). Estimates from the 4 methods were triangulated to provide a MID range across PROMIS domain: 2.5 to 6.5 T-score points for physical function and fatigue, 2.5 to 7.5 for social role satisfaction, and 3.0 to 8.0 for anxiety. Cumulative distribution functions plots identified between 30% and 40% of patients as having meaningful improvement based on the anchor-based estimates across all 4 domains. Meaningful change thresholds remained consistent across categories of sex and race. Anchor-based MIDs increased with increasing severity, whereas distribution-based MIDs remained consistent across severity levels. CONCLUSIONS: Our study is the first to evaluate interpretability of changes in PROMIS scores for stroke survivors. Future studies can utilize these thresholds to identify responders of stroke interventions. Based on our estimated MID ranges, researchers and clinicians can choose a responder threshold for comparing change in domain score at the group level, individual level, or by severity.
A Phase 2 Randomized, Sham-Controlled Trial of Internal Carotid Artery Infusion of Autologous Bone Marrow-Derived ALD-401 Cells in Patients With Recent Stable Ischemic Stroke (RECOVER-Stroke).
Savitz SI, Yavagal D, Rappard G … +10 more , Likosky W, Rutledge N, Graffagnino C, Alderazi Y, Elder JA, Chen PR, Budzik RF, Tarrel R, Huang DY, Hinson JM
Circulation · 2019 Jan · PMID 30586746 · Publisher ↗
BACKGROUND: Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The p...
BACKGROUND: Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The primary objective of this trial was to determine the safety of internal carotid artery, intra-arterially delivered autologous bone marrow-derived ALD-401 in patients with disabling middle cerebral artery stroke in comparison with sham harvest with sham infusion. Secondary objectives were to determine feasibility and efficacy. METHODS: This was a prospective phase 2, industry-funded, randomized, sham-controlled, parallel-group, multicenter study with blinded assessments. One hundred subjects were planned, aged 30 to 83 years, with confirmed first-time middle cerebral artery ischemic stroke with modified Rankin scale ≥3. Study patients were randomly assigned 3:2 to bone marrow harvest at 11 to 17 days after stroke followed 2 days later by intracarotid infusion of ALD-401 versus sham harvest and then sham infusion in the same timeframe. The primary study outcome was safety based on the incidence of a 4-point National Institutes of Health Stroke Scale worsening and the proportion of serious adverse events. Efficacy was based on modified Rankin scale change at 90 days. Other secondary outcomes were the proportions of patients experiencing adverse events, disability by Barthel Index, quality of life using EQ-5D, rehabilitation utilization, disability at 1 year, and MRI evidence of complications. RESULTS: There were no infusional or allergic reactions and no difference in treatment emergent adverse events. Four patients had small areas of asymptomatic restricted diffusion on MRI in the treatment group. There was no significant difference between the ALD-401 and placebo groups on the modified Rankin scale for the intent-to-treat population at day 90 (mean difference, 0.3; 95% CI, -0.3 to 0.8; P=0.330). There were no significant differences between the groups on any of the secondary efficacy measures. CONCLUSIONS: Intracarotid infusion of ALD-401 does not lead to clinical adverse events in patients with subacute ischemic stroke, although there was a higher incidence of small lesions on MRI in the treatment group. There was no difference in the primary efficacy end point between the groups. The study provides a framework for the design and conduct of future intra-arterial cell therapy trials in stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01273337.
Refining Prediction of Atrial Fibrillation-Related Stroke Using the P-CHADS-VASc Score.
Maheshwari A, Norby FL, Roetker NS … +11 more , Soliman EZ, Koene RJ, Rooney MR, O'Neal WT, Shah AM, Claggett BL, Solomon SD, Alonso A, Gottesman RF, Heckbert SR, Chen LY
Circulation · 2019 Jan · PMID 30586710 · Full text
BACKGROUND: In people with atrial fibrillation (AF), periods of sinus rhythm present an opportunity to detect prothrombotic atrial remodeling through measurement of P-wave indices (PWIs)-prolonged P-wave duration, abnorm...
BACKGROUND: In people with atrial fibrillation (AF), periods of sinus rhythm present an opportunity to detect prothrombotic atrial remodeling through measurement of P-wave indices (PWIs)-prolonged P-wave duration, abnormal P-wave axis, advanced interatrial block, and abnormal P-wave terminal force in lead V1. We hypothesized that the addition of PWIs to the CHADS-VASc score would improve its ability to predict AF-related ischemic stroke. METHODS: We included 2229 participants from the ARIC study (Atherosclerosis Risk in Communities) and 700 participants from MESA (Multi-Ethnic Study of Atherosclerosis) with incident AF who were not on anticoagulants within 1 year of AF diagnosis. PWIs were obtained from study visit ECGs before development of AF. AF was ascertained using study visit ECGs and hospital records. Ischemic stroke cases were based on physician adjudication of hospital records. We used Cox proportional hazards models to estimate hazard ratios and 95% CIs of PWIs for ischemic stroke. Improvement in 1-year stroke prediction was assessed by C-statistic, categorical net reclassification improvement, and relative integrated discrimination improvement. RESULTS: Abnormal P-wave axis was the only PWI associated with increased ischemic stroke risk (hazard ratio, 1.84; 95% CI, 1.33-2.55) independent of CHADS-VASc variables, and that resulted in meaningful improvement in stroke prediction. The β estimate was approximately twice that of the CHADS-VASc variables, and thus abnormal P-wave axis was assigned 2 points to create the P-CHADS-VASc score. This improved the C-statistic (95% CI) from 0.60 (0.51-0.69) to 0.67 (0.60-0.75) in ARIC and 0.68 (0.52-0.84) to 0.75 (0.60-0.91) in MESA (validation cohort). In ARIC and MESA, the categorical net reclassification improvements (95% CI) were 0.25 (0.13-0.39) and 0.51 (0.18-0.86), respectively, and the relative integrated discrimination improvement (95% CI) were 1.19 (0.96-1.44) and 0.82 (0.36-1.39), respectively. CONCLUSIONS: Abnormal P-wave axis-an ECG correlate of left atrial abnormality- improves ischemic stroke prediction in AF. Compared with CHADS-VASc, the P-CHADS-VASc is a better prediction tool for AF-related ischemic stroke.
Genetically Determined Levels of Circulating Cytokines and Risk of Stroke.
Georgakis MK, Gill D, Rannikmäe K … +10 more , Traylor M, Anderson CD, Lee JM, Kamatani Y, Hopewell JC, Worrall BB, Bernhagen J, Sudlow CLM, Malik R, Dichgans M
Circulation · 2019 Jan · PMID 30586705 · Full text
BACKGROUND: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective wa...
BACKGROUND: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether genetically determined circulating levels of cytokines and growth factors are associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study. METHODS: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study of 8293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67 162 cases; 454 450 controls) applying inverse variance-weighted meta-analysis, weighted-median analysis, Mendelian randomization-Egger regression, and multivariable Mendelian randomization. The UK Biobank cohort was used as an independent validation sample (4985 cases; 364 434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits by using publicly available genome-wide association study data. RESULTS: Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (odds ratio [OR] per 1 SD increase, 1.06; 95% CI, 1.02-1.09; P=0.0009), any ischemic stroke (OR, 1.06; 95% CI, 1.02-1.10; P=0.002), large-artery stroke (OR, 1.19; 95% CI, 1.09-1.30; P=0.0002), and cardioembolic stroke (OR, 1.14; 95% CI, 1.06-1.23; P=0.0004), but not with small-vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR, 1.08; 95% CI, 0.99-1.17; P=0.09; any ischemic stroke: OR, 1.07; 95% CI, 0.97-1.18; P=0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR, 1.04; 95% CI, 1.00-1.08; P=0.04) and myocardial infarction (OR, 1.05; 95% CI, 1.01-1.09; P=0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in patients with stroke in comparison with controls. CONCLUSIONS: Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, in particular with large-artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study.
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