Clonal Hematopoiesis Is Associated With Higher Risk of Stroke

Background and Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease–related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. Methods: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes ( DNMT3A , TET2 , and ASXL1 ) with any stroke, ischemic stroke, and hemorrhagic stroke. Results: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03–1.27]; P =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01–1.51]; P =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. Conclusions: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

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Age at Menopause and Risk of Ischemic and Hemorrhagic Stroke

Stroke ◽

10.1161/strokeaha.120.030558 ◽

2021 ◽

Author(s):

Sabrina J.G.C. Welten ◽

N. Charlotte Onland-Moret ◽

Jolanda M.A. Boer ◽

W.M. Monique Verschuren ◽

Yvonne T. van der Schouw

Keyword(s):

Risk Factor ◽

Ischemic Stroke ◽

Hemorrhagic Stroke ◽

Stroke Risk ◽

Cox Regression ◽

Hazard Ratio ◽

Natural Menopause ◽

Age At Menopause ◽

Increased Risk ◽

Surgical Menopause

Background and Purpose: The few epidemiological studies that addressed the association between age at menopause and ischemic and hemorrhagic stroke risk in women had conflicting findings. We aimed to investigate whether age at (natural and surgical) menopause is a risk factor for total, ischemic, and hemorrhagic stroke in women. Methods: We analyzed data from 16 244 postmenopausal women, aged 26 to 70 years at recruitment who were enrolled in the European Prospective Investigation into Cancer and Nutrition–Netherlands cohort between 1993 and 1997. Participants were followed for the occurrence of stroke until January 1, 2011. At baseline, participants filled in questionnaires about health, reproductive history including age at menopause, diet, and lifestyle. Cox regression was used to investigate the association between age at menopause and stroke. All analyses were adjusted for age, smoking, systolic blood pressure, and body mass index. Results: Mean age of menopause was 46.4 (7.0) years. A total of 830 strokes (571 ischemic, 162 hemorrhagic, 97 unclassified) were identified. Earlier menopause was associated with an increased risk of total stroke. Compared with women who experienced menopause between 50 and 54 years old, women who underwent menopause before age 40 years had 1.48× higher risk (95% CI, 1.19–1.85) of total stroke. In continuous analyses, we observed a 2% lower total stroke risk for each year menopause was delayed (hazard ratio, 0.98 [95% CI, 0.97–0.99]). The risk between earlier menopause and stroke was confined to ischemic stroke, earlier menopause was not associated with hemorrhagic stroke. The association with age at menopause was stronger for natural menopause (hazard ratio <40 versus 50–54 years, 1.74 [95% CI, 1.12–2.70]) than for surgical menopause (hazard ratio <40 versus 50–54 years, 1.26 [95% CI, 0.84–1.89]). Conclusions: The risk of total and ischemic stroke decreased with an increase in age at menopause. Whether this should have clinical consequences such as intensified risk factor control should be subject of further studies.

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Blood Pressure Level and Variability During Long-Term Prasugrel or Clopidogrel Medication After Stroke

Stroke ◽

10.1161/strokeaha.120.032824 ◽

2021 ◽

Vol 52 (4) ◽

pp. 1234-1243

Author(s):

Kazunori Toyoda ◽

Hiroshi Yamagami ◽

Kazuo Kitagawa ◽

Takanari Kitazono ◽

Takehiko Nagao ◽

...

Keyword(s):

Blood Pressure ◽

Ischemic Stroke ◽

Hemorrhagic Stroke ◽

Recurrent Stroke ◽

Hazard Ratio ◽

Observational Period ◽

Bleeding Events ◽

Increased Risk ◽

Ischemic Events

Background and Purpose: High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied. Methods: This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP. Results: A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094–1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010–1.466]), hemorrhagic stroke (13 events, 3.247 [1.660–6.296]), ischemic events (142 events, 1.219 [1.020–1.466]), and bleeding events (47 events, 1.629 [1.172–2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220–4.225] per 10-mm Hg increase; 3.051 [2.179–4.262]; 3.276 [1.172–9.092]; 2.865 [2.042–4.011]; 2.764 [1.524–5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP. Conclusions: Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp ; Unique identifier: JapicCTI-111582.

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A study of prevalence of migraine in stroke patients and its association with ischemic versus hemorrhagic stroke: a cross sectional study

International Journal of Advances in Medicine ◽

10.18203/2349-3933.ijam20200660 ◽

2020 ◽

Vol 7 (3) ◽

pp. 470

Author(s):

Paridhi Shivde ◽

Chandrahas Patidar ◽

Umesh Kumar Chandra ◽

Archana Verma ◽

Sumit Kumar Vishwakarma

Keyword(s):

Risk Factor ◽

Ischemic Stroke ◽

Hemorrhagic Stroke ◽

Cross Sectional Study ◽

Sectional Study ◽

Autonomic Nervous System Dysfunction ◽

Cross Sectional ◽

Increased Risk ◽

History Of ◽

Patient’S History

Background: Migraine is characterized by recurrent attacks of disabling headache and autonomic nervous system dysfunction. Up to one third of patients also have neurological aura symptoms. It has been suggested that migraine can be a risk factor for stroke. Migraine affects three times the number of women than men. The incidence of stroke in men is two times that of women. It is shown in several studies that women aged 35 to 45 years old are at increased risk of ischemic stroke who had migraine with or without aura.Methods: The present cross sectional study was conducted in 350 consecutive patients of stroke who were attended OPD and admitted in wards of the Department of Medicine, M.G.M. Medical College and MY Hospital, Indore, MP, India, during period from December 2017 to December 2018.Results: The highest percentage of respondents i.e. 68% belonged to male group followed by 32% of respondents who were females. The highest percentage of respondents i.e. 66.6% had ischemic stroke while, 33.4% had hemorrhagic stroke. The highest percentage of respondents i.e. 90.9% had no Migraine while, 9.1% had Migraine. The highest percentage of respondents i.e. 31.2% had weekly reoccurrence, followed by forth nightly (25%) and lowest was 3.1% of daily recurrence. The association of type of stroke with sex group of patient’s history of headache which found to be significant (p ˂0.05). The association of type of stroke with sex group of patient’s history of various cerebro-vascular risk factors which found to be significant (p<0.05). Patients having hemorrhagic and ischemic stroke also had HTN in 47% and 12.4% patients respectively.Conclusions: In this study it is concluded that migraine can be established as a risk factor for ischemic stroke. Early diagnosis and treatment with available medication can be helpful in prevention or decreasing risk for developing stroke.

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Interacting evolutionary pressures drive mutation dynamics and health outcomes in aging blood

10.1101/2020.04.25.058677 ◽

2020 ◽

Author(s):

Kimberly Skead ◽

Armande Ang Houle ◽

Sagi Abelson ◽

Mawusse Agbessi ◽

Vanessa Bruat ◽

...

Keyword(s):

Negative Selection ◽

Sequence Data ◽

Relative Proportion ◽

Selective Advantage ◽

Driver Mutations ◽

Driver Genes ◽

Hematopoietic Stem ◽

Age Related ◽

Increased Risk ◽

Passenger Mutations

AbstractA small population of self-renewing, hematopoietic stem cells continuously reconstitutes our immune system. As we age, these cells, or their pluripotent descendants, accumulate somatic mutations; some of these mutations provide selection advantages and increase in frequency in the peripheral blood cell population. This process of positive selection, deemed age-related clonal hematopoiesis (ARCH), is associated with increased risk for cardiac disease and blood malignancies, like acute myeloid leukemia (AML). However, it remains unclear why some people with ARCH do not progress to AML, even when their blood cells harbor well-known AML driver mutations. Here, we examine whether negative selection can play a role in determining AML progression by modelling the complex interplay of positive and negative selective processes. Using a novel approach combining deep learning and population genetic models, we detect pervasive negative selection in targeted sequence data from the blood of 92 pre-AML individuals and 385 healthy controls. We find that the relative proportion of passenger to driver mutations is critical in determining if the selective advantage conferred to a cell by a known driver mutation is able to overwhelm negative selection acting on passenger mutations and allow clones harbouring disease-predisposing mutations to rise to dominance. We find that a subset of non-driver genes is enriched for mildly damaging mutations in healthy individuals fitting purifying models of evolution suggesting that mutations in these genes might confer a protective role against disease-predisposing clonal expansions. Through exploring non drivercentric models of evolution, we show how different classes of evolution act to shape hematopoietic dynamics and subsequent health outcome which may better inform disease prediction and unveil novel therapeutic targets. We anticipate that our results and modelling techniques can be broadly applied to identify both driver mutations and those mildly damaging passenger mutations, as well as help understand the early evolution of cancer in other cells and tissues.

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Association of ADH1B polymorphism and alcohol consumption with increased risk of intracerebral hemorrhagic stroke

Journal of Translational Medicine ◽

10.1186/s12967-021-02904-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Chun-Hsiang Lin ◽

Oswald Ndi Nfor ◽

Chien-Chang Ho ◽

Shu-Yi Hsu ◽

Disline Manli Tantoh ◽

...

Keyword(s):

Ischemic Stroke ◽

Alcohol Consumption ◽

Genetic Variants ◽

Regression Models ◽

Hemorrhagic Stroke ◽

Alcohol Exposure ◽

Modifiable Risk Factors ◽

Aldehyde Dehydrogenase 2 ◽

Logistic Regression Models ◽

Increased Risk

Abstract Background Alcohol consumption is one of the modifiable risk factors for intracerebral hemorrhage, which accounts for approximately 10–20% of all strokes worldwide. We evaluated the association of stroke with genetic polymorphisms in the alcohol metabolizing genes, alcohol dehydrogenase 1B (ADH1B, rs1229984) and aldehyde dehydrogenase 2 (ALDH2, rs671) genes based on alcohol consumption. Methods Data were available for 19,500 Taiwan Biobank (TWB) participants. We used logistic regression models to test for associations between genetic variants and stroke. Overall, there were 890 individuals with ischemic stroke, 70 with hemorrhagic stroke, and 16,837 control individuals. Participants with ischemic but not hemorrhagic stroke were older than their control individuals (mean ± SE, 58.47 ± 8.17 vs. 48.33 ± 10.90 years, p < 0.0001). ALDH2 rs671 was not associated with either hemorrhagic or ischemic stroke among alcohol drinkers. However, the risk of developing hemorrhagic stroke was significantly higher among ADH1B rs1229984 TC + CC individuals who drank alcohol (odds ratio (OR), 4.85; 95% confidence interval (CI) 1.92–12.21). We found that the test for interaction was significant for alcohol exposure and rs1229984 genotypes (p for interaction = 0.016). Stratification by alcohol exposure and ADH1B rs1229984 genotypes showed that the risk of developing hemorrhagic stroke remained significantly higher among alcohol drinkers with TC + CC genotype relative to those with the TT genotype (OR, 4.43, 95% CI 1.19–16.52). Conclusions Our study suggests that the ADH1B rs1229984 TC + CC genotype and alcohol exposure of at least 150 ml/week may increase the risk of developing hemorrhagic stroke among Taiwanese adults.

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HIV is associated with an increased risk of age-related clonal hematopoiesis among older adults

Nature Medicine ◽

10.1038/s41591-021-01357-y ◽

2021 ◽

Author(s):

Nila J. Dharan ◽

Paul Yeh ◽

Mark Bloch ◽

Miriam M. Yeung ◽

David Baker ◽

...

Keyword(s):

Older Adults ◽

Clonal Hematopoiesis ◽

Age Related ◽

Increased Risk

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Abstract T P136: Potential Contributors to the Declining Impact of Stroke Risk Factors with Age: Implications for Stroke Epidemiology in the Elderly

Stroke ◽

10.1161/str.45.suppl_1.tp136 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

George Howard ◽

Mary Cushman ◽

Maciej Banach ◽

Brett M Kissela ◽

David C Goff ◽

...

Keyword(s):

Risk Factors ◽

Risk Factor ◽

Stroke Risk ◽

Multivariable Analysis ◽

The Elderly ◽

Stroke Risk Factors ◽

Age Related ◽

Increased Risk ◽

The Impact ◽

Age Related Changes

Purpose: The importance of stroke research in the elderly is increasing as America is “graying.” For most risk factors for most diseases (including stroke), the magnitude of association with incident events decreases at older ages. Potential changes in the impact of risk factors could be a “true” effect, or could be due to methodological issues such as age-related changes in residual confounding. Methods: REGARDS followed 27,748 stroke-free participants age 45 and over for an average of 5.3 years, during which 715 incident strokes occurred. The association of the “Framingham” risk factors (hypertension [HTN], diabetes, smoking, AFib, LVH and heart disease) with incident stroke risk was assessed in age strata of 45-64 (Young), 65-74 (Middle), and 75+ (Old). For those with and without an “index” risk factor (e.g., HTN), the average number of “other” risk factors was calculated. Results: With the exception of AFib, there was a monotonic decrease in the magnitude of the impact across the age strata, with HTN, diabetes, smoking and LVH even becoming non-significant in the elderly (Figure 1). However, for most factors, the increasing prevalence of other risk factors with age impacts primarily those with the index risk factor absent (Figure 2, example HTN as the “index” risk factor). Discussion: The impact of stroke risk factors substantially declined at older ages. However, this decrease is partially attributable to increases in the prevalence of other risk factors among those without the index risk factor, as there was little change in the prevalence of other risk factors in those with the index risk factor. Hence, the impact of the index risk factor is attenuated by increased risk in the comparison group. If this phenomenon is active with latent risk factors, estimates from multivariable analysis will also decrease with age. A deeper understanding of age-related changes in the impact of risk factors is needed.

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Abstract 79: Troponin T, NT-proBNP, and Incidence of Stroke: The Atherosclerosis Risk in Communities (ARIC) Study

Stroke ◽

10.1161/str.44.suppl_1.a79 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Aaron R Folsom ◽

Vijay Nambi ◽

Elizabeth J Bell ◽

Oludamilola W Oluleye ◽

Rebecca F Gottesman ◽

...

Keyword(s):

Ischemic Stroke ◽

General Population ◽

Troponin T ◽

High Sensitivity ◽

Hazard Ratio ◽

Cardioembolic Stroke ◽

Atherosclerosis Risk In Communities ◽

Increased Risk ◽

Atherosclerosis Risk ◽

Aric Study

Increased levels of plasma troponins and natriuretic peptides in the general population are associated with increased future risk of cardiovascular disease, but only limited information exists on these biomarkers and stroke occurrence. In a prospective epidemiological study, the Atherosclerosis Risk in Communities (ARIC) Study, we tested the hypothesis that high-sensitivity troponin T (TnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are associated positively with incidence of stroke. We measured plasma high-sensitivity TnT and NT-proBNP in 10,902 men or women initially free of stroke and followed them for a mean of 11.3 years for stroke occurrence (n=507). Analyses were performed using proportional hazards modeling. Both biomarkers were associated positively with total stroke, nonlacunar ischemic, and especially, cardioembolic stroke, but not with lacunar or hemorrhagic stroke. After adjustment for other stroke risk factors, the hazard ratio (95% CI) per one SD greater increment of natural log-transformed TnT was 1.23 (1.13, 1.35) for total stroke, 1.27 (1.15, 1.40) for total ischemic stroke, and 1.36 (1.14, 1.62) for cardioembolic stroke. Likewise, the hazard ratio per one SD greater natural log-transformed NT-proBNP, was 1.37 (1.26, 1.49) for total stroke, 1.39 (1.27, 1.53) for total ischemic stroke, and 1.95 (1.67, 2.28) for cardioembolic stroke. The hazard ratios for jointly high values of TnT (≥0.013 ug/L) and NT-proBNP (≥155.2 pg/mL), versus neither biomarker high, were 2.70 (1.92, 3.79) for total stroke and 6.26 (3.40, 11.5) for cardioembolic stroke, and somewhat stronger for NT-proBNP than TnT. Strikingly, approximately 58% of cardioembolic strokes occurred in the highest quintile of pre-stroke NT-proBNP (versus 3% occurring in the lowest quintile), and 32% of cardioembolic strokes occurred in participants who had both NT-proBNP in the highest quintile and were known by ARIC to have atrial fibrillation sometime before their cardioembolic stroke occurrence. In conclusion, in the general population, elevated plasma TnT and NT-proBNP concentrations are associated with increased risk of cardioembolic and other nonlacunar ischemic strokes.

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Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22189867 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9867

Author(s):

Yi-Chun Huang ◽

Chao-Yung Wang

Keyword(s):

Cardiovascular Disease ◽

Dna Methyltransferase ◽

Gene Mutations ◽

Cvd Risk ◽

Telomere Attrition ◽

Clonal Hematopoiesis ◽

Age Related ◽

Cell Clones ◽

Important Relationship ◽

Increased Risk

Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere–CHIP–atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.

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Traffic-borne pollution as a risk factor for acute vascular events: a population study in Milan

European Journal of Public Health ◽

10.1093/eurpub/ckaa165.085 ◽

2020 ◽

Vol 30 (Supplement_5) ◽

Author(s):

P Magnoni ◽

R Murtas ◽

A G Russo

Keyword(s):

Risk Factor ◽

Ischemic Stroke ◽

Hemorrhagic Stroke ◽

Proportional Hazards ◽

Traffic Noise ◽

Cox Proportional Hazards ◽

Positive Trend ◽

Traffic Intensity ◽

Vascular Events ◽

Remarkable Effect

Abstract Background Traffic-borne noise and air pollution have both been associated with cardiovascular and cerebrovascular diseases, albeit with inconsistent findings and issues of collinearity/mutual confounding. The present study aims at evaluating the role of long-term exposure to traffic-borne pollution as a risk factor for acute vascular events in a highly urbanized setting. Methods This is a population-based retrospective dynamic cohort study including all residents aged >35 years in the municipality of Milan over the years 2011-2018 (N = 1087110). A noise predictive model and a NO2 land-use regression model were used to assign mean values of traffic noise at the day-evening-night level (Lden, dB) and NO2 concentration (µg/m3) to the residential address of each subject. Cox proportional hazards models were performed to assess the incidence of acute vascular events, with adjustment for potential confounders (age, sex, nationality, a socio-economic deprivation index) and sub-analyses for different outcomes (acute myocardial infarction, ischemic stroke, hemorrhagic stroke). Results A total of 27282 subjects (2.5%) had an acute vascular event. Models using NO2 yielded inconsistent results. When using Lden as a proxy of traffic intensity, there was a positive trend in risk with increasing levels of exposure, with an optimal cut-off for dichotomization set at 70 dB (HR 1.025, 95% C.I. 1.000-1.050). The association was observed specifically for ischemic stroke (HR 1.043, 95% C.I. 1.003-1.085) and hemorrhagic stroke (HR 1.036, 95% C.I. 0.969-1.107). When stratifying by age group and sex, a remarkable effect was found for hemorrhagic stroke in men aged <60 (HR 1.439, 95% C.I. 1.156-1.792). Conclusions Living close to high-traffic roads was found to exert a small but tangible effect on the risk of stroke. The varying effects observed for specific outcomes and in different age and sex groups are likely due to different pathogenetic mechanisms at play, which warrant further investigation. Key messages Residential proximity to roads with high traffic intensity (mean traffic noise level over 70 dB) is a risk factor for stroke, especially for hemorrhagic stroke in middle-aged men. Further interventions aimed at reducing traffic intensity in highly urbanized cities may be justified in order to reduce morbidity and mortality from stroke.

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