Echocardiographic and Clinical Risk Factors for Atrial Fibrillation in Hypertensive Patients With Ischemic Stroke

Background: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in five trials across the spectrum of cardiometabolic disease. Methods: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48, SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, and FOURIER trials were included in this analysis. A set of 32 SNPs associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. Results: In 51,288 subjects across the five trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, increasing genetic risk was strongly and independently associated with increased risk for ischemic stroke (p-trend=0.009). When compared to individuals in the lowest third of genetic risk, individuals in the middle and top tertiles of genetic risk had adjusted hazard ratios of 1.15 (95% CI 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted HR for the top versus lowest tertile of 1.27 (95% CI 1.04-1.53), compared with an adjusted HR of 1.06 (95% CI 0.81-1.41) in subjects with prior stroke. In an exploratory analysis of patients with atrial fibrillation and CHA 2 DS 2 -VASc of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA 2 DS 2 -VASc of 3. Conclusions: Across a broad spectrum of subjects with cardiometabolic disease, a 32-SNP GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA 2 DS 2 -VASc scores, the GRS identified patients with risk comparable to those with higher CHA 2 DS 2 -VASc scores.

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Combining Clinical and Polygenic Risk Improves Stroke Prediction Among Individuals with Atrial Fibrillation

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003168 ◽

2021 ◽

Author(s):

Jack W. O'Sullivan ◽

Anna Shcherbina ◽

Johanne M. Justesen ◽

Mintu Turakhia ◽

Marco Perez ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Ischemic Stroke ◽

Predictive Ability ◽

Clinical Risk Factors ◽

Risk Scores ◽

Polygenic Risk ◽

Clinical Risk ◽

Increased Risk ◽

The Uk

Background - Atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable, however current risk stratification tools (CHA 2 DS 2 -VASc) don't include family history or genetic risk. We hypothesized that we could improve ischemic stroke prediction in patients with AF by incorporating polygenic risk scores (PRS). Methods - Using data from the largest available GWAS in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank, both independently and integrated with clinical risk factors. The integrated PRS and clinical risk factors risk tool had the greatest predictive ability. Results - Compared with the currently recommended risk tool (CHA 2 DS 2 -VASc), the integrated tool significantly improved net reclassification (NRI: 2.3% (95%CI: 1.3% to 3.0%)), and fit (χ2 P =0.002). Using this improved tool, >115,000 people with AF would have improved risk classification in the US. Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (Hazard Ratio: 1.13 per 1 SD (95%CI: 1.06 to 1.23)). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearson's correlation coefficient: -0.018). Conclusions - In patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors, however the prediction of stroke remains challenging.

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Cholesterol reducer and Thrombolytic therapy in acute ischemic stroke

10.21203/rs.2.20629/v1 ◽

2020 ◽

Author(s):

Nicolas Poupore ◽

Dan Strat ◽

Tristan Mackey ◽

Katherine Brown ◽

Ashley Snell ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Demographic Data ◽

Recombinant Tissue Plasminogen Activator ◽

Clinical Risk Factors ◽

Medication History ◽

Factors Associated ◽

Clinical Risk

Abstract Background Specific clinical risk factors may contribute to worsening or improving neurological functions in an acute ischemic stroke (AIS) patient pre-treated with a cholesterol reducer with a subsequent recombinant tissue plasminogen activator (rtPA) treatment. We investigated clinical risk factors associated with good or poor presenting neurological symptoms in ischemic stroke patients with prior cholesterol reducer use, specifically a statin and rtPA therapy.Methods We retrospectively analyzed baseline clinical and demographic data of 630 patients with AIS taking cholesterol reducers prior to rtPA treatment from January 2010 to June 2016 in a regional stroke center. Progressing (NIHSS ≤ 7) or worsening (NIHSS > 7) scores for neurologic improvement determined measures for treatment outcome. Multivariate logistic regression models identified demographic and clinical factors associated with worsening or progressing neurologic functions.Results Adjusted multivariate analysis showed that in an ischemic stroke population with a combined rtPA and cholesterol reducer medication history, increasing age (OR = 1.032, 95% CI, 1.015-1.048, P < 0.001) and atrial fibrillation (OR = 1.859, 95% CI, 1.098-3.149, P = 0.021) demonstrated a likely association with worsening neurologic functions, while direct admission (OR = 0.411, 95% CI, 0.246-0.686, P = 0.001) and being Caucasian (OR = 0.496, 95% CI, 0.297-0.827, P = 0.007) showed an association with improving or progressing neurologic functions.Conclusion A prior cholesterol reducer, namely a statin, plus rtPA combination may be associated with worsening neurological function for elderly AIS patients with atrial fibrillation, while Caucasians directly admitted to a neurology unit are more likely to show an association with progress or improvements in neurologic functions.

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Abstract 13771: Combining Clinical and Polygenic Risk Improves Stroke Prediction Among Individuals With Atrial Fibrillation

Circulation ◽

10.1161/circ.142.suppl_3.13771 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Jack W Osullivan ◽

Anna Shcherbina ◽

Johanne M Justesen ◽

Mintu Turakhia ◽

Marco V Perez ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Ischemic Stroke ◽

Predictive Ability ◽

Clinical Risk Factors ◽

Risk Scores ◽

Uk Biobank ◽

Polygenic Risk ◽

Clinical Risk ◽

Increased Risk

Introduction: Atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable, however current risk stratification tools (CHA 2 DS 2 -VASc) don’t include family history or genetic risk. Hypothesis: A polygenic risk scores (PRS) is both independently, and in integrated with clinical risk factors, predictive of ischemic stroke in patients with Atrial Fibrillation. Methods: Using data from the largest available GWAS in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank (UK Biobank), both independently and integrated with clinical risk factors. Results: The integrated PRS and clinical risk factors risk tool had the greatest predictive ability. Compared with the currently recommended risk tool (CHA 2 DS 2 -VASc), the integrated tool significantly improved net reclassification (NRI: 2.3% (95%CI: 1.3% to 3.0%)), and fit (χ2 P =0.002). Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (Hazard Ratio: 1.13 per 1 SD (95%CI: 1.04 to 1.21)). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearson’s correlation coefficient: -0.018). Conclusions: In patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors, however the prediction of stroke remains challenging.

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Cholesterol reducer and thrombolytic therapy in acute ischemic stroke patients

10.21203/rs.2.20629/v2 ◽

2020 ◽

Author(s):

Nicolas Poupore ◽

Dan Strat ◽

Tristan Mackey ◽

Katherine Brown ◽

Ashley Snell ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Demographic Data ◽

Clinical Risk Factors ◽

Stroke Patients ◽

Medication History ◽

Factors Associated ◽

Clinical Risk

Abstract Background Specific clinical risk factors may contribute to worsening or improving neurological functions in an acute ischemic stroke (AIS) patient pre-treated with a cholesterol reducer with a subsequent recombinant tissue plasminogen activator (rtPA) treatment. We investigated clinical risk factors associated with good or poor presenting neurological symptoms in ischemic stroke patients with prior cholesterol reducer use, specifically a statin and rtPA therapy. Methods We retrospectively analyzed baseline clinical and demographic data of 630 patients with AIS taking cholesterol reducers prior to rtPA treatment from January 2010 to June 2016 in a regional stroke center. Progressing (NIHSS ≤ 7) or worsening (NIHSS > 7) scores for neurologic improvement determined measures for treatment outcome. Multivariate logistic regression models identified demographic and clinical factors associated with worsening or progressing neurologic functions. Results Adjusted multivariate analysis showed that in an ischemic stroke population with a combined rtPA and cholesterol reducer medication history, increasing age (OR = 1.032, 95% CI, 1.015-1.048, P < 0.001) and atrial fibrillation (OR = 1.859, 95% CI, 1.098-3.149, P = 0.021) demonstrated a likely association with worsening neurologic functions, while direct admission (OR = 0.411, 95% CI, 0.246-0.686, P = 0.001) and being Caucasian (OR = 0.496, 95% CI, 0.297-0.827, P = 0.007) showed an association with improving or progressing neurologic functions. Conclusion A prior cholesterol reducer, namely a statin, plus rtPA combination may be associated with worsening neurological function for elderly AIS patients with atrial fibrillation, while Caucasians directly admitted to a neurology unit are more likely to show an association with progress or improvements in neurologic functions.

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Combining clinical and polygenic risk improves stroke prediction among individuals with atrial fibrillation

10.1101/2020.06.17.20134163 ◽

2020 ◽

Author(s):

Jack W. O’Sullivan ◽

Anna Shcherbina ◽

Johanne M Justesen ◽

Mintu Turakhia ◽

Marco Perez ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Ischemic Stroke ◽

Predictive Ability ◽

Clinical Risk Factors ◽

Risk Scores ◽

Uk Biobank ◽

Polygenic Risk ◽

Clinical Risk ◽

Increased Risk

AbstractBackgroundAtrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable, however current risk stratification tools (CHA2DS2-VASc) don’t include family history or genetic risk. We hypothesized that we could improve ischemic stroke prediction in patients with AF by incorporating polygenic risk scores (PRS).ObjectivesTo construct and test a PRS to predict ischemic stroke in patients with AF, both independently and integrated with clinical risk factors.MethodsUsing data from the largest available GWAS in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank (UK Biobank), both independently and integrated with clinical risk factors.ResultsThe integrated PRS and clinical risk factors risk tool had the greatest predictive ability. Compared with the currently recommended risk tool (CHA2DS2-VASc), the integrated tool significantly improved net reclassification (NRI: 2.3% (95%CI: 1.3% to 3.0%)), and fit (χ2 P =0.002). Using this improved tool, >115,000 people with AF would have improved risk classification in the US. Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (Hazard Ratio: 1.13 per 1 SD (95%CI: 1.06 to 1.23))). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearson’s correlation coefficient: −0.018).ConclusionsIn patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors, however the prediction of stroke remains challenging.

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Ischemic stroke with a preceding Trans ischemic attack(TIA) less than 24 hours: Predicting clinical risk factors for thrombolytic therapy

10.21203/rs.2.17137/v1 ◽

2019 ◽

Author(s):

Nicolas Poupore ◽

Dan Strat ◽

Tristan Mackey ◽

Ashley Snell ◽

Thomas Nathaniel

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Thrombolytic Therapy ◽

Older Patients ◽

Clinical Risk Factors ◽

Receiver Operating Curve ◽

Stroke Patients ◽

Clinical Risk ◽

Stroke Population ◽

Clinical Risks

Abstract Background Acute ischemic stroke attack with and without a recent TIA within or less than 24 hours may differ in clinical risk factors, and this may affect treatment outcomes following thrombolytic therapy. We examined whether the odds of exclusion or inclusion for thrombolytic therapy are greater in ischemic stroke with TIA less than 24 hours preceding ischemic stroke(TIA-24hr-ischemic stroke patients) as compared to those without recent TIA or non-TIA <24 hours.Methods A retrospective hospital-based analysis was conducted on 6,315 ischemic stroke patients, of whom 846 had proven brain diffusion-weighted magnetic resonance imaging (DW-MRI) of an antecedent TIA within 24 hours prior to ischemic stroke. The logistic regression model was developed to generate odds ratios (OR) to determine clinical factors that may increase the likelihood of exclusion or inclusion for thrombolytic therapy. The validity of the model was tested using a Hosmer-Lemeshow test, while the Receiver Operating Curve (ROC) was used to test the sensitivity of our model.Results In TIA-24hr-ischemic stroke population, patients with a history of alcohol abuse (OR = 5.525, 95% CI, 1.003-30.434, p = 0.05), migraine (OR=4.277, 95% CI, 1.095-16.703, p=0.037), and increasing NIHSS score (OR=1.156, 95% CI, 1.058-1.263, p = 0.001) were associated with the increasing odds of receiving rtPA, while older patients (OR = 0.965, 95% CI, 0.934‐0.997, P = 0.033) were associated with the increasing odds of not receiving rtPA.Conclusion In TIA-24hr-ischemic stroke patients, older patients with higher INR values are associated with increasing odds of exclusion from thrombolytic therapy. Our findings demonstrate clinical risks factors that can be targeted to improve the use and eligibility for rtPA in in TIA-24hr-ischemic stroke patients.

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Can clinical risk factors predict functional recovery in ischemic stroke patients with pre-stroke depression?

10.21203/rs.2.10087/v1 ◽

2019 ◽

Author(s):

Leah Wormack ◽

Brice Blum ◽

Benjamin Bailes ◽

Thomas Nathaniel

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Functional Outcome ◽

Clinical Risk Factors ◽

Stroke Patients ◽

Antihypertensive Medications ◽

Clinical Risk ◽

Predictive Variables ◽

Stroke Population ◽

Thrombolysis Therapy

Abstract Background. Specific clinical risk factors that may be associated with ambulatory outcome following thrombolysis therapy in ischemic stroke patients with pre-stroke depression is not fully understood. This was investigated. Methods. Multivariate analyses were performed to identify predictors of functional ambulatory outcomes. Patient demographics and clinical risk factors served as predictive variables, while improvement or no improvement in ambulatory outcome was considered as the primary outcome. Results. A total of 595 of these patients received rtPA of which 310 patients presented with pre-stroke depression, 217 had no improvement in functional outcome, while 93 patients presented with an improvement in functional outcome. Carotid artery stenosis (OR= 11.577, 95% CI, 1.281 – 104.636, P=0.029) and peripheral vascular disease (OR= 18.040, 95% CI, 2.956-110.086, P=0.002) were more likely to be associated with an improvement in ambulation. Antihypertensive medications (OR= 7.810, 95% CI, 1.401 –43.529, P=0.019),previous TIA (OR= 0.444, 95% CI, 0.517 –0.971, P=0.012), and congestive heart failure (OR= 0.217, 95% CI, 0.318 –0.402, P=0.030) were associated with a no improvement in ambulation. Conclusion. After adjustment for covariates, more clinical risk factors were associated with no improvement when compared with improvement in functional outcome following thrombolysis therapy in an acute ischemic stroke population with pre-stroke depression.

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