Introduction
A cardiovascular accident or stroke is a nervous system disorder characterized by blood vessel obstruction. The clot formation in the brain interrupts blood flow, clogging arteries and blood vessel rupture. Rupture of the blood vessels results in sudden cell death due to oxygen deficit. As a result, stroke leads to depression, memory loss, brain damage, or even death. There are two types of stroke:
-
Ischemic Stroke: It is caused by blood vessel blockage due to a blood clot.
-
Hemorrhagic Stroke: it is caused by a bleeding blood vessel in the brain.
Another condition, transient ischemic attack (TIA), is sometimes called a "mini-stroke." A TIA occurs when the brain’s blood supply is blocked for a short time. If a patient has a TIA, the risk of stroke is higher in the future.
What Is the Pathophysiology of a Cardiovascular Accident?
A stroke is an abrupt neurological occurrence caused by impaired perfusion to the blood vessels of the brain. One must understand the brain anatomy to study the clinical manifestation of stroke. The brain blood supply is maintained by two internal carotid arteries anteriorly (at the front) and two vertebral arteries posteriorly (at the back). The disease mechanisms of the two types of strokes are given below.
1. Ischemic Stroke: Ischemic (reduced blood flow to a body part) stroke contributes to around 85 percent of deaths in stroke patients. Ischemic occlusion generates thrombotic (clotting) and embolic (clot dislodgement) brain conditions. The blood flow gets obstructed by the narrowing of vessels due to atherosclerosis (plaque build-up) in thrombosis. The plaque build-up constricts the blood vessels and forms clots, causing a thrombotic stroke. Further, decreased blood circulation to the brain reduces blood flow to the brain, causing stress and necrosis (cell death).
Necrosis is followed by cell membrane disruption and organelle (small structure in the cell) swelling. As a result, it leads to the leaking of cellular contents into extracellular space and loss of nerve function. Other key events contributing to ischemic stroke are inflammation, energy failure, loss of homeostasis, increased calcium levels in the cell, free radical-mediated damage, blood-brain barrier (BBB) impairment, activation of immune cells, oxidative stress, and infiltration of white blood cells. However, mechanisms that need elaboration are:
-
Endothelial Dysfunction: Although several disease mechanisms are involved in ischemic stroke, endothelial dysfunction is the most important. The endothelium (blood vessel lining) regulates vessel tone, clotting activity, inflammation, and angiogenesis (new blood vessel formation). Its dysfunction reflects a shift towards a vasoconstrictive, pro-coagulation, and proinflammatory state. The details of this shift are unclear and result from aging, oxidative stress, genetic predisposition, and hypertension (increased blood pressure). The endothelium suffers structural and functional damage, leading to leakage and inflammation. Further damage leads to impaired oxygen supply to the brain. The vessel wall thickens as connective tissue replaces blood vessel wall layers with narrowing, thrombosis, and occlusion.
-
Blood-Brain Barrier Impairment: BBB is a blood vessel and tissue network of closely spaced cells that keep harmful substances from entering the brain. However, BBB allows water, oxygen, carbon dioxide, and general anesthetics to pass into the brain. In addition to other mechanisms, BBB degradation has a critical role in ischemic stroke. The BBB comprises endothelial cells, cell membranes, perivascular spaces (around the blood vessels), and immune cells. In a study to assess BBB permeability, patients with ischemic stroke underwent magnetic resonance imaging (MRI, an imaging technique) at that time and after three years. Poor functional outcome was associated with increased BBB permeability. Further evidence states that BBB leakage mediates stroke, and the severity of leakage is linked to hypertension.
-
Deranged Calcium Levels: Ischemia leads to interrupted intracellular (in the cell) calcium balance. As a result, there is a rapid influx of calcium into the cell. Elevated intracellular calcium activates various enzymes leading to free fatty acids (FFAs) production, including arachidonic acid (AA). In addition, FFAs have other degradative effects on cell membranes. AA is oxygenated by enzymes leading to the formation of inflammatory mediators. The inflammatory mediators are tissue irritants that cause platelet aggregation, clotting, and swelling, leading to impaired blood flow restoration to the brain.
Awareness of the participation of calcium in the ischemic cascade has led to the development of several neuroprotective agents to modify its role in ischemic stroke. However, it is not very successful because of several types of calcium channels. However, there is a definite role of calcium movement leading to the triggering of the cascade of events and nerve cell death.
-
Oxidative Stress and Inflammation: Oxidative stress is important in the pathology of ischemic stroke and is critical for the ischemic injury cascade in the brain. Oxidative stress leads to cell and brain death due to free radical injury. Superoxide anion, hydroxyl, and nitric oxide (NO) free radicals are produced during oxidative stress, which can cause inflammation and apoptosis (cell death). Excessive ROS react with surrounding molecules such as lipids, proteins, sugar, and deoxyribonucleic acid (DNA) through various reactions, which affect cell function and cause cell death. The toxic mechanism of ROS includes damaging endothelial cells and increased permeability in the BBB due to their high reactivity to lipids and proteins. ROS further mediates inflammation and immune response by stimulating the expression of inflammatory mediators, leading to brain tissue injury.
Inflammatory factors stimulate inflammation and aggravate ischemic injury. However, the mechanisms between oxidative stress, inflammation, and ischemic stroke interactions are unknown. Still, cerebral ischemia injury can lead to functional impairment. It leads to further dysfunction after blood supply recovery. Hence, oxidative stress and inflammation play critical roles in ischemic stroke.
2. Hemorrhagic Stroke: Hemorrhagic stroke accounts for about ten to 15 percent of all strokes and has a high death rate. It comprises intracerebral (ICH) and subarachnoid hemorrhage (SAH). In ICH, blood vessels break, leading to abnormal blood accumulation within the brain. The main reasons are raised blood pressure, disturbed vasculature (arrangement of blood vessels), and excessive use of anticoagulants (anti-clotting medications). In SAH, blood accumulates within the subarachnoid space (the space between membranes of the brain) due to a head injury or a brain aneurysm (abnormal widening of a blood vessel).
Conclusion
Stroke is known to cause death and disability with a significant global economic burden. There is an increased understanding of stroke pathophysiology and the studies targeting multiple pathways causing stroke. Still, the inability to translate research into clinical settings has hampered advances in stroke research. The challenges for researchers are to characterize the mechanisms underlying therapies, generate reproducible data, perform trials, and increase the practical value of the data before proceeding to clinical studies.
