Beyond the Brain: The Systemic Pathophysiological Response to Acute Ischemic Stroke

Abstract

Stroke research has traditionally focused on the cerebral processes following ischemic brain injury, where oxygen and glucose deprivation incite prolonged activation of excitatory neurotransmitter receptors, intracellular calcium accumulation, inflammation, reactive oxygen species proliferation, and ultimately neuronal death. A recent growing body of evidence, however, points to far-reaching pathophysiological consequences of acute ischemic stroke. Shortly after stroke onset, peripheral immunodepression in conjunction with hyperstimulation of autonomic and neuroendocrine pathways and motor pathway impairment result in dysfunction of the respiratory, urinary, cardiovascular, gastrointestinal, musculoskeletal, and endocrine systems. These end organ abnormalities play a major role in the morbidity and mortality of acute ischemic stroke. Using a pathophysiology-based approach, this current review discusses the pathophysiological mechanisms following ischemic brain insult that result in end organ dysfunction. By characterizing stroke as a systemic disease, future research must consider bidirectional interactions between the brain and peripheral organs to inform treatment paradigms and develop effective, comprehensive therapeutics for acute ischemic stroke.

Keywords: Disease progression; Pathologic processes; Physiopathology; Stroke; Translational medical research.

Figure 1.

The multi-systems effect of ischemic stroke. Ischemic stroke deprives the brain of sufficient blood flow, prompting a cascade of neurotoxic events that result in inflammation, neurotoxicity, and cell death (gray box). In addition to the resultant cerebrovascular injury, the pathophysiological consequences of ischemic stroke reach outside of the central nervous system and orchestrate organism-wide dysfunction. In this figure, the complexity of stroke pathophysiology is viewed through the lens of human body systems. The unconstrained influence of detrimental consequences reaches cardiac, endocrine, gastrointestinal, lymphoid, and musculoskeletal tissues, highlighting the bidirectional crosstalk between the brain and each affected organ system, and supporting the labeling of stroke as a systemic disease.

Figure 2.

Timeline of systemic complications following stroke. Systemic responses to ischemic stroke present clinically within hours and continue developing well beyond hospital discharge. Though some are transient in nature, many complications progress chronically into the months and years that follow. This timeline summarizes the onset and evolution windows of clinical manifestations (e.g., pneumonia) and associated pathologies (e.g., immunosuppression). Brain graphic created with BioRender. ^*Denotes predictors of poor outcome.

Figure 3.

The pathophysiological sequelae of ischemic stroke. The impact of ischemic stroke reaches systemic proportions through evolution of three main pathophysiologies: stroke-induced immunodepression, autonomic and neuroendocrine dysfunction, and motor pathway disruption (flow chart). Each pathophysiology then facilitates development of the detrimental clinical complications observed beyond the stroke-affected brain (Venn diagram). Though much overlap exists between influential pathophysiologies and the ensuing complications, this figure presents a simplified overview of how the pathophysiological sequelae of ischemic stroke culminates in a vast array of clinical complications. GI, gastrointestinal; DVT, deep vein thrombosis; PE, pulmonary embolism; DAMP, damage-associated molecular pattern; SNS, sympathetic nervous system; HPA, hypothalamic pituitary adrenal axis; PNS, parasympathetic nervous system; GALT, gut-associated lymphoid tissue.

Figure 4.

Ischemic stroke: a systemic disease overview. An overview of the key points, as detailed in this review, is presented in a summary box.