ADAMTS7 and ZC3HC1 Share Genetic Predisposition to Coronary Artery Disease and Large Artery Ischemic Stroke

Background: There is little information concerning the invasive coronary angiography (ICA) findings of patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) with elevated troponin levels and suspected myocardial infarction (MI). This study analyzed patient characteristics associated with ICA outcomes.Methods: A total of 8,322 patients with AIS or TIA, treated between March 2010 and May 2020, were retrospectively screened for elevated serum troponin I at hospital admission. Patients in whom ICA was performed, due to suspected type 1 MI based on symptoms, echocardiography, and ECG, were categorized according to ICA results (non-obstructive coronary artery disease (CAD): ≥1 stenosis ≥50% but no stenosis ≥80%; obstructive CAD: any stenosis ≥80% or hemodynamically relevant stenosis assessed by FFR/iwFR).Results: Elevated troponin levels were detected in 2,205 (22.5%) patients, of whom 123 (5.6%) underwent ICA (mean age 71 ± 12 years; 67% male). CAD was present in 98 (80%) patients, of whom 51 (41%) were diagnosed with obstructive CAD. Thus, ICA findings of obstructive CAD accounted for 2.3% of patients with troponin elevation and 0.6% of all stroke patients. The clinical hallmarks of myocardial ischemia, including angina pectoris (31 vs. 15%, p < 0.05) and regional wall motion abnormalities (49 vs. 32%, p = 0.07), and increased cardiovascular risk indicated obstructive CAD. While there was no association between lesion site or stroke severity and ICA findings, causal large-artery atherosclerosis was significantly more common in patients with obstructive coronary disease (p < 0.05).Conclusion: The rate of obstructive CAD in patients with stroke or TIA and elevated troponin levels with suspected concomitant type I MI is low. The cumulation of several cardiovascular risk factors and clinical signs of MI were predictive. AIS patients with large-artery atherosclerosis and elevated troponin may represent an especially vulnerable subgroup of stroke patients with risk for obstructive CAD.

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Predictors and Functional Outcomes of Fast, Intermediate, and Slow Progression Among Patients With Acute Ischemic Stroke

Stroke ◽

10.1161/strokeaha.120.030010 ◽

2020 ◽

Vol 51 (8) ◽

pp. 2553-2557 ◽

Cited By ~ 2

Author(s):

Woo-Keun Seo ◽

David S. Liebeskind ◽

Bryan Yoo ◽

Latisha Sharma ◽

Reza Jahan ◽

...

Keyword(s):

Coronary Artery Disease ◽

Ischemic Stroke ◽

Coronary Artery ◽

Functional Outcomes ◽

Artery Occlusion ◽

Large Artery ◽

Anterior Circulation ◽

Endovascular Thrombectomy ◽

Ischemic Core ◽

Artery Disease

Background and Purpose: We aimed to delineate the determinants of the initial speed of infarct progression and the association of speed of infarct progression (SIP) with procedural and functional outcomes. Methods: From a prospectively maintained stroke center registry, consecutive anterior circulation ischemic stroke patients with large artery occlusion, National Institutes of Health Stroke Scale score ≥4, and multimodal vessel, ischemic core, and tissue-at-risk imaging within 24 hours of onset were included. Initial SIP was calculated as ischemic core volume at first imaging divided by the time from stroke onset to imaging. Results: Among the 88 patients, SIP was median 2.2 cc/h (interquartile range, 0–8.7), ranging most widely within the first 6 hours after onset. Faster SIP was positively independently associated with a low collateral score (odds ratio [OR], 3.30 [95% CI, 1.25–10.49]) and arrival by emergency medical services (OR, 3.34 [95% CI, 1.06–10.49]) and negatively associated with prior ischemic stroke (OR, 0.12 [95% CI, 0.03–0.50]) and coronary artery disease (OR, 0.32 [95% CI, 0.10–1.00]). Among the 67 patients who underwent endovascular thrombectomy, slower SIP was associated with a shift to reduced levels of disability at discharge (OR, 3.26 [95% CI, 1.02–10.45]), increased substantial reperfusion by thrombectomy (OR, 8.30 [95% CI, 0.97–70.87]), and reduced radiological hemorrhagic transformation (OR, 0.34 [95% CI, 0.12–0.94]). Conclusions: Slower SIP is associated with a high collateral score, prior ischemic stroke, and coronary artery disease, supporting roles for both collateral robustness and ischemic preconditioning in fostering tissue resilience to ischemia. Among patients undergoing endovascular thrombectomy, the speed of infarct progression is a major determinant of clinical outcome.

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Risk stratification for large artery or chronic coronary artery disease-related ischemic stroke in octogenarians undergoing exercise stress myocardial perfusion imaging: A cohort study

Journal of Nuclear Cardiology ◽

10.1007/s12350-015-0361-7 ◽

2015 ◽

Vol 24 (2) ◽

pp. 591-595 ◽

Cited By ~ 1

Author(s):

Athanasios Katsikis ◽

Athanasios Theodorakos ◽

Alexandros Drosatos ◽

Konstantinos Konstantinou ◽

Spyridon Papaioannou ◽

...

Keyword(s):

Coronary Artery Disease ◽

Cohort Study ◽

Ischemic Stroke ◽

Coronary Artery ◽

Exercise Stress ◽

Large Artery ◽

Stress Myocardial Perfusion Imaging ◽

Chronic Coronary Artery Disease ◽

Stress Myocardial Perfusion ◽

Artery Disease

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Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study

10.1101/19007682 ◽

2019 ◽

Cited By ~ 1

Author(s):

Marios K. Georgakis ◽

Rainer Malik ◽

Dipender Gill ◽

Nora Franceschini ◽

Cathie L. M. Sudlow ◽

...

Keyword(s):

Coronary Artery Disease ◽

Ischemic Stroke ◽

Coronary Artery ◽

Lower Risk ◽

Mendelian Randomization ◽

Cardiovascular Outcomes ◽

Small Vessel ◽

List Type ◽

Large Artery ◽

Artery Disease

ABSTRACTBackgroundStudies in humans and experimental models highlight a role of interleukin-6 (IL-6) in cardiovascular disease. Indirect evidence suggests that inhibition of IL-6 signaling could lower risk of coronary artery disease. However, whether such an approach would be effective for ischemic stroke and other cardiovascular outcomes remains unknown.MethodsIn a genome-wide association study (GWAS) of 204,402 European individuals, we identified genetic proxies for downregulated IL-6 signaling as genetic variants in the IL-6 receptor (IL6R) locus that were associated with lower C-reactive protein (CRP) levels, a downstream effector of IL-6 signaling. We then applied two-sample Mendelian randomization (MR) to explore associations with ischemic stroke and its major subtypes (large artery stroke, cardioembolic stroke, small vessel stroke) in the MEGASTROKE dataset (34,217 cases and 404,630 controls), with coronary artery disease in the CARDIoGRAMplusC4D dataset (60,801 cases and 123,504 control), and with other cardiovascular outcomes in the UK Biobank (up to 321,406 individuals) and in phenotype-specific GWAS datasets. All effect estimates were scaled to the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R.ResultsWe identified 7 genetic variants as proxies for downregulated IL-6 signaling, which showed effects on upstream regulators (IL-6 and soluble IL-6R levels) and downstream effectors (CRP and fibrinogen levels) of the pathway that were consistent with pharmacological blockade of IL-6R. In MR, proxies for downregulated IL-6 signaling were associated with lower risk of ischemic stroke (Odds Ratio [OR]: 0.89, 95%CI: 0.82-0.97) and coronary artery disease (OR: 0.84, 95%CI: 0.77-0.90). Focusing on ischemic stroke subtypes, we found significant associations with risk of large artery (OR: 0.76, 95%CI: 0.62-0.93) and small vessel stroke (OR: 0.71, 95%CI: 0.59-0.86), but not cardioembolic stroke (OR: 0.95, 95%CI: 0.74-1.22). Proxies for IL-6 signaling inhibition were further associated with a lower risk of myocardial infarction, aortic aneurysm, atrial fibrillation and carotid plaque.ConclusionsWe provide evidence for a causal effect of IL-6 signaling on ischemic stroke, particularly large artery and small vessel stroke, and a range of other cardiovascular outcomes. IL-6R blockade might represent a valid therapeutic target for lowering cardiovascular risk and should thus be investigated in clinical trials.CLINICAL PERSPECTIVEWhat is newWe identified genetic proxies for downregulated IL-6 signaling that had effects on upstream and downstream regulators of the IL-6 signaling pathway consistent with those of pharmacological IL-6R blockadeGenetically downregulated IL-6 signaling was associated with a lower risk of ischemic stroke, and in particular large artery and small vessel strokeSimilar associations were obtained for a broad range of other cardiovascular outcomesWhat are the clinical implicationsInhibition of IL-6 signaling is a promising therapeutic target for lowering risk of stroke and other cardiovascular outcomes and should be further investigated in clinical trials

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Cardiac Risk Factors for Stroke: A Comprehensive Mendelian Randomization Study

Stroke ◽

10.1161/strokeaha.121.036306 ◽

2021 ◽

Author(s):

Simon Frerich ◽

Rainer Malik ◽

Marios K. Georgakis ◽

Moritz F. Sinner ◽

Steven J. Kittner ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Genetic Predisposition ◽

Mendelian Randomization ◽

Genetic Data ◽

Cardiac Risk ◽

Large Artery ◽

Artery Disease

Background and Purpose: Observational studies suggest an association of stroke with cardiac traits beyond atrial fibrillation, the leading source of cardioembolism. However, controversy remains regarding a causal role of these traits in stroke pathogenesis. Here, we leveraged genetic data to systematically assess associations between cardiac traits and stroke risk using a Mendelian Randomization framework. Methods: We studied 66 cardiac traits including cardiovascular diseases, magnetic resonance imaging–derived cardiac imaging, echocardiographic imaging, and electrocardiographic measures, as well as blood biomarkers in a 2-sample Mendelian Randomization approach. Genetic predisposition to each trait was explored for associations with risk of stroke and stroke subtypes in data from the MEGASTROKE consortium (40 585 cases/406 111 controls). Using multivariable Mendelian Randomization, we adjusted for potential pleiotropic or mediating effects relating to atrial fibrillation, coronary artery disease, and systolic blood pressure. Results: As expected, we observed strong independent associations between genetic predisposition to atrial fibrillation and cardioembolic stroke and between genetic predisposition to coronary artery disease as a proxy for atherosclerosis and large-artery stroke. Our data-driven analyses further indicated associations of genetic predisposition to both heart failure and lower resting heart rate with stroke. However, these associations were explained by atrial fibrillation, coronary artery disease, and systolic blood pressure in multivariable analyses. Genetically predicted P-wave terminal force in V1, an electrocardiographic marker for atrial cardiopathy, was inversely associated with large-artery stroke. Conclusions: Available genetic data do not support substantial effects of cardiac traits on the risk of stroke beyond known clinical risk factors. Our findings highlight the need to carefully control for confounding and other potential biases in studies examining candidate cardiac risk factors for stroke.

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Physical activity, sedentary behavior and risk of coronary artery disease, myocardial infarction and ischemic stroke: a two-sample Mendelian randomization study

Clinical Research in Cardiology ◽

10.1007/s00392-021-01846-7 ◽

2021 ◽

Author(s):

Martin Bahls ◽

Michael F. Leitzmann ◽

André Karch ◽

Alexander Teumer ◽

Marcus Dörr ◽

...

Keyword(s):

Physical Activity ◽

Myocardial Infarction ◽

Coronary Artery Disease ◽

Ischemic Stroke ◽

Coronary Artery ◽

Sedentary Behavior ◽

Mendelian Randomization ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Artery Disease

Abstract Aims Observational evidence suggests that physical activity (PA) is inversely and sedentarism positively related with cardiovascular disease risk. We performed a two-sample Mendelian randomization (MR) analysis to examine whether genetically predicted PA and sedentary behavior are related to coronary artery disease, myocardial infarction, and ischemic stroke. Methods and results We used single nucleotide polymorphisms (SNPs) associated with self-reported moderate to vigorous PA (n = 17), accelerometer based PA (n = 7) and accelerometer fraction of accelerations > 425 milli-gravities (n = 7) as well as sedentary behavior (n = 6) in the UK Biobank as instrumental variables in a two sample MR approach to assess whether these exposures are related to coronary artery disease and myocardial infarction in the CARDIoGRAMplusC4D genome-wide association study (GWAS) or ischemic stroke in the MEGASTROKE GWAS. The study population included 42,096 cases of coronary artery disease (99,121 controls), 27,509 cases of myocardial infarction (99,121 controls), and 34,217 cases of ischemic stroke (404,630 controls). We found no associations between genetically predicted self-reported moderate to vigorous PA, accelerometer-based PA or accelerometer fraction of accelerations > 425 milli-gravities as well as sedentary behavior with coronary artery disease, myocardial infarction, and ischemic stroke. Conclusions These results do not support a causal relationship between PA and sedentary behavior with risk of coronary artery disease, myocardial infarction, and ischemic stroke. Hence, previous observational studies may have been biased. Graphic abstract

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Association between the PPP1R3B polymorphisms and serum lipid traits, the risk of coronary artery disease and ischemic stroke in a southern Chinese Han population

Nutrition & Metabolism ◽

10.1186/s12986-018-0266-y ◽

2018 ◽

Vol 15 (1) ◽

Cited By ~ 2

Author(s):

Wei-Jun Li ◽

Rui-Xing Yin ◽

Jian-Hua Huang ◽

Yuan Bin ◽

Wu-Xian Chen ◽

...

Keyword(s):

Coronary Artery Disease ◽

Ischemic Stroke ◽

Coronary Artery ◽

Serum Lipid ◽

Chinese Han Population ◽

Chinese Han ◽

Han Population ◽

Southern Chinese ◽

Artery Disease

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Genetic variant at coronary artery disease and ischemic stroke locus 1p32.2 regulates endothelial responses to hemodynamics

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1810568115 ◽

2018 ◽

Vol 115 (48) ◽

pp. E11349-E11358 ◽

Cited By ~ 15

Author(s):

Matthew D. Krause ◽

Ru-Ting Huang ◽

David Wu ◽

Tzu-Pin Shentu ◽

Devin L. Harrison ◽

...

Keyword(s):

Coronary Artery Disease ◽

Ischemic Stroke ◽

Coronary Artery ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

Enhancer Activity ◽

Protective Allele ◽

Unidirectional Flow ◽

Artery Disease

Biomechanical cues dynamically control major cellular processes, but whether genetic variants actively participate in mechanosensing mechanisms remains unexplored. Vascular homeostasis is tightly regulated by hemodynamics. Exposure to disturbed blood flow at arterial sites of branching and bifurcation causes constitutive activation of vascular endothelium contributing to atherosclerosis, the major cause of coronary artery disease (CAD) and ischemic stroke (IS). Conversely, unidirectional flow promotes quiescent endothelium. Genome-wide association studies (GWAS) have identified chromosome 1p32.2 as strongly associated with CAD/IS; however, the causal mechanism related to this locus remains unknown. Using statistical analyses, assay of transposase accessible chromatin with whole-genome sequencing (ATAC-seq), H3K27ac/H3K4me2 ChIP with whole-genome sequencing (ChIP-seq), and CRISPR interference in human aortic endothelial cells (HAECs), our results demonstrate that rs17114036, a common noncoding polymorphism at 1p32.2, is located in an endothelial enhancer dynamically regulated by hemodynamics. CRISPR-Cas9–based genome editing shows that rs17114036-containing region promotes endothelial quiescence under unidirectional shear stress by regulating phospholipid phosphatase 3 (PLPP3). Chromatin accessibility quantitative trait locus (caQTL) mapping using HAECs from 56 donors, allelic imbalance assay from 7 donors, and luciferase assays demonstrate that CAD/IS-protective allele at rs17114036 in PLPP3 intron 5 confers increased endothelial enhancer activity. ChIP-PCR and luciferase assays show that CAD/IS-protective allele at rs17114036 creates a binding site for transcription factor Krüppel-like factor 2 (KLF2), which increases the enhancer activity under unidirectional flow. These results demonstrate that a human SNP contributes to critical endothelial mechanotransduction mechanisms and suggest that human haplotypes and related cis-regulatory elements provide a previously unappreciated layer of regulatory control in cellular mechanosensing mechanisms.

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