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Associating cryptogenic ischemic stroke in the young with cardiovascular risk factor phenotypes.

ABSTRACT: Acute Ischemic Stroke (AIS) in the young is increasing in prevalence and the largest subtype within this cohort is cryptogenic. To curb this trend, new ways of defining cryptogenic stroke and associated risk factors are needed. We aimed to gain insights into the presence or absence of cardiovascular risk factors in cases of cryptogenic stroke. We conducted a retrospective cohort study of patients aged 18-49 who presented to an urban tertiary care center with AIS. We manually collected predefined demographic, clinical, laboratory and radiological variables. Clinical risk phenotypes were determined using these variables through multivariate analysis of patients with the small and large vessel disease subtypes (vascular phenotype) and cardioembolic subtype (cardiac phenotype). The resultant phenotype models were applied to cases deemed cryptogenic. Within the 449 patients who met criteria, patients with small and large vessel disease (vascular phenotype) had higher rates of hypertension, intracranial atherosclerosis, and diabetes mellitus, and higher admission glucose, HbA1c, admission blood pressure, and cholesterol compared to the patients with cardioembolic AIS. The cardioembolic subgroup (cardiac phenotype) had significantly higher rates of congestive heart failure (CHF), rheumatic heart disease, atrial fibrillation, clotting disorders, left ventricular hypertrophy, larger left atrial sizes, lower ejection fractions, and higher B-type natriuretic peptide and troponin levels. Adjusted multivariate analysis produced six variables independently associated with the vascular phenotype (age, male sex, hemoglobin A1c, ejection fraction (EF), low-density lipoprotein (LDL) cholesterol, and family history of AIS) and five independently associated with the cardiac phenotype (age, female sex, decreased EF, CHF, and absence of intracranial atherosclerosis). Applying these models to cryptogenic stroke cases yielded that 51.5% fit the vascular phenotype and 3.1% fit the cardiac phenotype. In our cohort, half of young patients with cryptogenic stroke fit the risk factor phenotype of small and large vessel strokes.

SUBMITTER: Dardick JM

PROVIDER: S-EPMC7801422 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Associating cryptogenic ischemic stroke in the young with cardiovascular risk factor phenotypes.

Dardick Joseph M JM Flomenbaum David D Labovitz Daniel L DL Cheng Natalie N Liberman Ava L AL Esenwa Charles C

Scientific reports 20210111 1

Acute Ischemic Stroke (AIS) in the young is increasing in prevalence and the largest subtype within this cohort is cryptogenic. To curb this trend, new ways of defining cryptogenic stroke and associated risk factors are needed. We aimed to gain insights into the presence or absence of cardiovascular risk factors in cases of cryptogenic stroke. We conducted a retrospective cohort study of patients aged 18-49 who presented to an urban tertiary care center with AIS. We manually collected predefined ...[more]

PMID: 33431950

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Project description:BACKGROUND:Up to 50% of ischemic strokes in the young after thorough diagnostic work-up remain cryptogenic or associated with low-risk sources of cardioembolism such as patent foramen ovale (PFO). We studied with cardiac magnetic resonance (CMR) imaging, whether left ventricular (LV) non-compaction-a possible source for embolic stroke due to sluggish blood flow in deep intertrabecular recesses-is associated with cryptogenic strokes in the young. METHODS:Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) is an international prospective multicenter case-control study of young adults (aged 18-49 years) presenting with an imaging-positive first-ever ischemic stroke of undetermined etiology. In this pilot substudy, 30 cases and 30 age- and sex-matched stroke-free controls were examined with CMR. Transcranial Doppler (TCD) bubble test was performed to evaluate the presence and magnitude of right-to-left shunt (RLS). RESULTS:There were no significant differences in LV volumes, masses or systolic function between cases and controls; none of the participants had non-compaction cardiomyopathy. Semi-automated assessment of LV non-compaction was highly reproducible. Non-compacted LV mass (median 14.0 [interquartile range 12.6-16.0] g/m2 vs. 12.7 [10.4-16.6] g/m2, p = 0.045), the ratio of non-compacted to compacted LV mass (mean 25.6 ± 4.2% vs. 22.8 ± 6.0%, p = 0.015) and the percentage of non-compacted LV volume (mean 17.6 ± 2.9% vs. 15.7 ± 3.8%, p = 0.004) were higher in cases compared to controls. In a multivariate conditional logistic regression model including non-compacted LV volume, RLS and body mass index, the percentage of non-compacted LV volume (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.10-2.18, p = 0.011) and the presence of RLS (OR 11.94, 95% CI 1.14-124.94, p = 0.038) were independently associated with cryptogenic ischemic stroke. CONCLUSIONS:LV non-compaction is associated with a heightened risk of cryptogenic ischemic stroke in young adults, independent of concomitant RLS and in the absence of cardiomyopathy. CLINICAL TRIAL REGISTRATION:SECRETO; NCT01934725. Registered 4th September 2013. https://clinicaltrials.gov/ct2/show/NCT01934725.

Project description:BackgroundThe prevalence of stroke in young adults is increasing. We investigated the monogenic basis of young adult cryptogenic stroke patients.MethodsThis multicenter study enrolled cryptogenic stroke patients under 55 years old, and individuals with nonstroke diseases were included as controls. Targeted next-generation sequencing (NGS) was applied with a custom-designed gene panel that included 551 genes. Rare variants were classified into 2 groups: pathogenic variants and variants of unknown significance.ResultsA total of 153 individuals, including 30 (21 males, 70%; mean age 36.1±10.2 years) in the disease group and 123 (59 males, 48.0%; mean age 40.4±13.1 years) in the control group, were recruited. In the disease group, 32 rare variants were identified. Among these individuals, 18 pathogenic variants in 16 patients were detected, with a 53.3% (16/30) diagnostic yield of monogenic causes for cryptogenic stroke. None of these mutations were observed in the control group. Among the mutant genes, the most prevalent were Notch receptor 3 (NOTCH3), protein kinase AMP-activated noncatalytic subunit gamma 2 (PRKAG2), and ryanodine receptor 2 (RYR2). Genes associated with cardiogenic diseases showed the highest mutation frequency (10/18, 55.6%) followed by genes associated with small-vessel diseases (SVDs) and coagulation disorders. None of the patients with mutations had evident abnormalities in the heart or other systems checked by routine tests. For the imaging phenotype-genotype association analysis, infarctions in both the anterior and posterior cerebral circulation were only observed in patients with genes related to cardiogenic disease.ConclusionsIn this study, pathogenic variants were identified in nearly half of the young-onset cryptogenic stroke patients, with genes related to cardiogenic diseases being the most frequently mutated. This may have implications for future clinical decision-making, including the development of finer and more sensitive examinations.

Dataset Information

Associating cryptogenic ischemic stroke in the young with cardiovascular risk factor phenotypes.

Publications

Associating cryptogenic ischemic stroke in the young with cardiovascular risk factor phenotypes.

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