American Heart Association

epidemiology and genetics

ISC 2021 Session: Substance Abuse in Stroke

Setareh Salehi Omran, MD

International Stroke Conference 2021
March 17–19, 2021
Session: Substance Abuse in Stroke (153, OnDemand)

The session “Substance Abuse in Stroke” at the International Stroke Conference 2021 included several presentations on the risk of stroke from a wide range of substances, including cannabis, tobacco cigarettes, e-cigarettes, alcohol, methamphetamine, and cocaine.

Marijuana and Synthetic Cannabinoid by Dr. Stephen Sidney:

Dr. Sidney discussed the potential mechanisms of cerebrovascular disease associated with cannabis use. Cannabis can lead to cerebrovascular disease through direct toxic effects on the vascular bed, altered hemodynamics (increased heart rate, increased supine blood pressure, postural hypotension), incident atrial fibrillation and atrial flutter, and endothelial dysfunction. Several studies have shown an association between cannabis exposure and increased risk of stroke. However, these studies have several major limitations, including cross-sectional study design, inability to stratify analysis by confounders (cigarette smoking, cocaine use), and lack of granular clinical information pertaining to the stroke and cannabis use (dose, composition, possible contaminants, various modes of consumption).

As it stands, it is unclear whether cannabis use is associated with stroke. It is important for clinicians to notify patients of limited data on cannabis use and stroke risk, and to advise against cannabis use in patients with known cardiovascular disease.

Stroke Plays Neither Fair, Nor Equal

Isabella Canavero, MD

Kamin Mukaz D, Zakai NA, Cruz-Flores S, McCullough LD, Cushman M. Identifying Genetic and Biological Determinants of Race-Ethnic Disparities in Stroke in the United States. Stroke. 2020;51:3417–3424.*

The hypothetical “democracy” of diseases potentially affecting everyone has to be retracted when analyzing real-world data. We must acknowledge that, actually, nothing is fair about diseases. Access to medical care, nutrition, socioeconomic status, and education are relevant factors in determining course and outcome of many diseases, especially in the vascular area. Stroke follows this rule: As compared to White people, other underrepresented racial-ethnic populations are featured by a disproportionately higher prevalence of traditional vascular risk factors (hypertension, diabetes, obesity above all).

Besides socioeconomic and cultural determinants of lifestyle resulting in vascular risk factors, Kamin Mukaz et al. explored genetic and biological factors partly accounting for the racial disparity of stroke by reviewing current evidence from large cohorts.

Does Gender Play a Role in TIA/Stroke Diagnosis?

Shashank Shekhar, MD, MS

Gocan S, Fitzpatrick T, Wang CQ, Taljaard M, Cheng W, Bourgoin A, Dowlatshahi D, Stotts G, Shamy M. Diagnosis of Transient Ischemic Attack: Sex-Specific Differences From a Retrospective Cohort Study. Stroke. 2020.

Sex differences might play a role in TIA/stroke diagnosis. Men and women could have variable TIA/stroke symptom characteristics. Women especially have been reported to have non-specific and atypical symptoms, which can result in a wrong diagnosis or no diagnosis. However, stroke in women tends to have a more severe and complicated course. The recent study by Gocan et al., published in Stroke, attempts to determine the relationship between clinical variables associated with a neurologist’s final diagnosis of TIA/stroke and the patient’s sex difference.

The authors conducted a retrospective analysis of the patient cohort from the Ottawa Hospital Stroke prevention clinic in 2015. The study identified 23 character variables for TIA/stroke diagnosis. Out of that, 15 variables were used, and the remaining eight were excluded due to the low frequency of occurrences.

Article Commentary: “Smoking Causes Fatal Subarachnoid Hemorrhage”

Deepak Gulati, MD

Rautalin I, Korja M, Kaprio J. Smoking Causes Fatal Subarachnoid Hemorrhage: A Case-Control Study of Finnish Twins. Stroke. 2020.

Smoking has been identified as the most important lifestyle risk factor for subarachnoid hemorrhage (SAH) and accounts for at least one third of all cases.

Familial risk is defined as the probability of a healthy family member being affected by the same disease that has already affected at least one other family member. Familial risk of SAH depends on a number of factors, including genetic and environmental factors. It has been a challenge to estimate the genetic risk of SAH in relatives given the relatively low incidence of SAH. The accurate estimation of genetic risk could have significant implications on prophylactic screening protocols of intracranial aneurysms. Large twin cohorts provide a “shortcut” to carry out the estimation of heritability. Twin studies usually provide the natural way to separate familial resemblance from genetic influence. The Nordic Twin Study in 2010 indicated that most twin pairs were discordant for SAH, i.e., only one twin died from SAH. However, the role of risk factors in explaining this discordance was not studied.

Article Commentary: “Trends in Stroke Recurrence in Mexican Americans and Non-Hispanic Whites”

Grace Y. Kuo, MD, MS, BA

Sozener CB, Lisabeth LD, Shafie-Khorassani F, Kim S, Zahuranec DB, Brown DL, Skolarus LE, Burke JF, Kerber KA, Meurer WJ, et al. Trends in Stroke Recurrence in Mexican Americans and Non-Hispanic Whites. Stroke. 2020.

Stroke prevention, treatment and management have crossed many milestones in the last 20 years in developed countries, with studies showing that recurrent strokes have declined over the last 50 years. As medical options become more publicly available, health disparities between those who have benefit from secondary stroke prevention become more apparent. Epidemiological data breaking down trends in stroke recurrence will be critical to public health planning as we strive for more equity in stroke care. In this article from the Brain Attack Surveillance in Corpus Cristi (BASIC) project, we see a glimpse of hope in closing the disparity gap.

This study examines the trend in stroke recurrence in an urban population in Nueces County, Texas, of Mexican Americans (MAs) and Non-Hispanic Whites (NHWs) over 14 years. The MA population are predominantly non-immigrant, second and third generation U.S. citizens, with low incidence of return migration. Patients were eligible for database enrollment if they were at least 45 years old and resided in Nueces County at least six months per year. Mortality data was obtained from the Texas Department of State Health Services.

Diabetes Mellitus, But Not Prediabetes, Associated With Poorer Cognitive Performance After Stroke

Lina Palaiodimou, MD

Lo JW, Crawford JD, Samaras K, Desmond DW, Köhler S, Staals J, et al. Association of Prediabetes and Type 2 Diabetes With Cognitive Function After Stroke: A STROKOG Collaboration Study. Stroke. 2020.

Diabetes mellitus (DM) affects about 422 million people and is one of the leading causes of death worldwide (World Health Organization). More importantly, the burden of type 2 diabetes (T2D) has been rising relentlessly in all countries in the past three decades. However, it is estimated that a significant percentage of cases of T2D remain undiagnosed. DM is one of the major modifiable risk factors for stroke. In addition, it has been associated with adverse outcomes after stroke, including higher mortality, poorer neurological and functional outcomes, longer hospital stay, higher readmission rates, and stroke recurrence. Another outcome, the post-stroke cognitive function, and its relationship with DM, are being evaluated in the STROKOG collaboration study.

Lo et al. for the STROKOG collaboration present a meta-analysis of individual participant data (IPD) derived from seven international post-stroke cohorts with the aim to investigate the relationship between T2M and prediabetes with cognitive impairment after stroke.

What About Stroke Primary Prevention? Article Commentary on “Hypothetical Lifestyle Strategies in Middle-Aged Women and the Long-Term Risk of Stroke”

Grace Y. Kuo, MD, MS, BA

Jain P, Suemoto C, Rexrode K, Manson J, Robins J, Hernan M, et al. Hypothetical Lifestyle Strategies in Middle-Aged Women and the Long-Term Risk of Stroke. Stroke. 2020.

We are fortunate enough to be in an era in which we have multiple validated treatments for stroke care. However, with the decrease in overall stroke incidence and mortality, we are beginning to see a gender disparity in the disease of stroke. More women, particularly in the elderly populations, suffer from stroke than men. Although it may be due to longer life expectancy for women, it is still important to look for strategies to decrease this disparity. Prospective studies have found an inverse association between healthy lifestyles and strokes. However, as the natural history of the chronic conditions that lead to strokes occurs over decades, the actual effects of lifestyle interventions for primary prevention are difficult to study in randomized trials.

The article “Hypothetical Lifestyle Strategies in Middle-Aged Women and the Long-Term Risk of Stroke” is an attempt to understand the effects of dietary and non-dietary modifications on stroke risk by using longitudinal observational data in a hypothetical analysis to estimate the possible risk reduction of the interventions. Data was obtained from the Nurse’s Health Study (NHS), a database that was started in 1976 with 121,701 participants. In 1984, the participants were sent a food frequency questionnaire (FFQ), which was used as a basis for dietary pattern. Based on this survey, 59,727 participants were deemed eligible, after exclusion criteria of having pre-existing cardiovascular events (stroke, MI, angina, history of CABG) and cancer. Incomplete surveys or surveys with implausible responses were also excluded from analysis. 1986, the first follow-up year, was set as the baseline year to allow for adjustment for pre-baseline confounders. Every two years thereafter, participants were sent follow-up questionnaires. Participants were followed until their first diagnosis of stroke, death or June 2012.

Sleep Disturbances and Increased Risk of Atherosclerosis in the Young

Raffaele Ornello, MD

Zhao YY, Javaheri S, Wang R, Guo N, Koo BB, Stein JH, et al. Associations Between Sleep Apnea and Subclinical Carotid Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis. Stroke. 2019;50:3340–3346.

Literature suggests that sleep disturbances, including sleep apnea (SA), are associated with an increased risk of stroke; however, the reasons for the association are unclear.

In their prospective observational study, the authors assessed the association between sleep disturbances and indirect markers of atherosclerosis, namely the carotid intima-media thickness (CIMT) and the presence of carotid plaque, in a multi-ethnic population of 1615 subjects aged 45-85 years. The authors found an association between SA and carotid plaque only in subjects younger than 68 years; on the other hand, decreased oxygen saturation during sleep was associated with an increase in CIMT, only in younger or black individuals.

The authors’ results suggest that the mechanisms linking sleep disturbances to carotid plaques and to increased CIMT are different and both more pronounced in younger individuals. However, the most relevant result of the study is perhaps a negative one: Habitual snoring was not associated with any increased risk of carotid atherosclerosis. The study findings are in line with the recently released 2019 AHA/ASA guidelines for the management of acute ischemic stroke, which recommend against systematic screening for SA in all patients with acute ischemic stroke.

Article Commentary: “Stroke Incidence and Case Fatality According to Rural or Urban Residence: Results From the French Brest Stroke Registry”

Kristina Shkirkova, BSc

Grimaud O, Lachkhem Y, Gao F, Padilla C, Bertin M, Nowak E, et al. Stroke Incidence and Case Fatality According to Rural or Urban Residence: Results From the French Brest Stroke Registry. Stroke. 2019;50:2661–2667.

In this entry, I discuss a recent publication by Olivier Grimaud and colleagues regarding the stroke incidence and case fatality according to rural or urban residence. Although rural-urban disparities in stroke epidemiology research have received modest attention in recent years, localization of most stroke registries in large urban areas confounds exploration of stroke mortality as a function of urban/rural area.

There has been conflicting evidence regarding the association between stroke incidence and rural or urban residence status. Recent data in the United States suggests that rural residence location is associated with higher incidence of stroke than urban location of residence. Similarly, results from other high-income countries also report conflicting data. The authors of this study sought to examine the relationship between stroke incidence, case fatality, and residence location using the French Brest Stroke Registry.

Article Commentary: “Leveraging Human Genetics to Estimate Clinical Risk Reductions Achievable by Inhibiting Factor XI”

Alan C. Cameron, MB ChB, BSc (Hons), MRCP

Georgi B, Mielke J, Chaffin M, Khera AV, Gelis L, Mundl H, et al. Leveraging Human Genetics to Estimate Clinical Risk Reductions Achievable by Inhibiting Factor XI. Stroke. 2019.

In this recent article, Georgi and colleagues highlight coagulation factor XI (FXI) as a promising new target for antithrombotic therapy to prevent ischemic stroke without an increased risk of major bleeding. The authors analyzed data from the UK Biobank and two large genome wide association studies to formulate a genetic score standardized to a 30% increase in relative activated partial thromboplastin time, which is equivalent to effects achieved by pharmacological FXI inhibition compared to enoxaparin for the prevention of venous thromboembolism after total knee arthroplasty. 

The results herald what could potentially be a game-changer in antithrombotic therapy for stroke prevention. The authors demonstrate that genetic predisposition to lower FXI levels is associated with a 53% reduction in risk of ischemic stroke (OR 0.47, 95% CI 0.36–0.61; p=1.5×10−8) and a 90% reduction in risk of venous thrombosis (OR 0.1, 95% CI 0.07–0.14; p=3.03×10−43) without an increase in major bleeding (OR 0.69, 95% CI 0.45–1.04; p=0.0739). The reductions in risk of ischemic stroke are similar in patients with or without a history of atrial fibrillation (AF), suggesting that absolute risk reductions are higher in patients with AF. The authors went on to apply a calibration factor to estimate the effects of genetically lower FXI levels compared to placebo and demonstrate an estimated risk reduction of 56% (OR 0.44, 95% CI 0.31–0.62); this is broadly comparable to relative risk reductions observed with warfarin compared to placebo.