Date of Award

January 2022

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Kevin N. Sheth

Second Advisor

Guido J. Falcone

Abstract

Intracerebral hemorrhage (ICH) is the most devastating and least treatable form of stroke, accounting for 50% of all stroke-related mortality and 30% of stroke-related costs. ICH is also the most severe consequence of cerebral small vessel disease (CSVD), a common neuroimaging finding that underlies many diseases of aging including dementia and frailty. The objectives of this multi-part thesis are to 1) describe trends in the epidemiology of ICH in the United States, 2) identify novel risk factors and prognostic factors in ICH using complimentary observational and genetic methods, 3) evaluate blood pressure lowering as a treatment for ICH, and 4) to improve our understanding of recovery and secondary prevention after ICH, with a focus on the role of hypertension in the role of vascular disease and brain health.

Part I evaluates trends in stroke epidemiology over time by age and geographic location in the United states. We found that stroke burden is decreasing in older adults nationwide but increasing in younger adults in the South and Midwest US, especially for ICH. Part II combines observational and genetic data to study chronic kidney disease (CKD) as a causal risk factor for ICH. We found that CKD and genetically-determined CKD were associated with 54% and 45% increases in the odds of ICH, respectively, independent of hypertension. Part III evaluates interleukin-6 (IL-6) as a prognostic biomarker in a clinical trial cohort and found that those in the highest IL-6 quartile after ICH had 2 times the odds of a poor outcome compared to the lowest quartile. Part IV determines hematoma volume cutoffs with maximal sensitivity and specificity for predicting poor outcome in hypertension-related ICH using receiver-operating curve analysis. We found that 8 mL and 18 mL predicted poor outcomes in thalamic and basal ganglia ICH, respectively. Part V tests whether the location, and thus underlying pathophysiology, of ICH modifies the effect of intensive blood pressure reduction on hematoma expansion in a post-hoc analysis of a clinical trial. We found a subgroup with deep, hypertension-related ICH that may benefit from this therapy. Part VI studies the risk of recurrent ICH in a longitudinal analysis of claims data using Cox proportional hazards regression and found disparities in ICH risk by race/ethnicity and insurance payer. Part VII explores reasons for poor blood pressure control after ICH and describes the low prevalence of hyperaldosteronism testing and diagnosis in a cohort of Veteran’s Affairs patients with ICH, and introduces a clinical trial of mineralocorticoid antagonism for blood pressure control after ICH.

Overall, this work highlights the central role of hypertension in ICH risk, severity, acute management, and recovery. Conditions that contribute to vascular comorbidities, including chronic kidney disease and systemic inflammation, likely influence both the risk and outcomes of ICH and should be evaluated as therapeutic targets. Further efforts focused on personalized blood pressure management are needed to improve the primary and secondary prevention of ICH. An intersectional approach between these factors and social determinants of health must be taken to improve the burden of ICH and health disparities in this disease.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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