Cerebral Autoregulation in Subarachnoid Hemorrhage

Abstract

Subarachnoid hemorrhage (SAH) is a devastating stroke subtype with a high rate of mortality and morbidity. The poor clinical outcome can be attributed to the biphasic course of the disease: even if the patient survives the initial bleeding emergency, delayed cerebral ischemia (DCI) frequently follows within 2 weeks time and levies additional serious brain injury. Current therapeutic interventions do not specifically target the microvascular dysfunction underlying the ischemic event and as a consequence, provide only modest improvement in clinical outcome. SAH perturbs an extensive number of microvascular processes, including the "automated" control of cerebral perfusion, termed "cerebral autoregulation." Recent evidence suggests that disrupted cerebral autoregulation is an important aspect of SAH-induced brain injury. This review presents the key clinical aspects of cerebral autoregulation and its disruption in SAH: it provides a mechanistic overview of cerebral autoregulation, describes current clinical methods for measuring autoregulation in SAH patients and reviews current and emerging therapeutic options for SAH patients. Recent advancements should fuel optimism that microvascular dysfunction and cerebral autoregulation can be rectified in SAH patients.

Keywords: cerebral blood flow; cystic fibrosis transmembrane conductance regulator; delayed ischemia; microvascular dysfunction; stroke.

Figure 1

Cerebral autoregulation. Cerebral autoregulation is plotted as a relationship between cerebral blood flow (CBF) and mean arterial pressure (MAP). The autoregulatory range is defined by MAP levels that elicit maximal myogenic vasodilation (lower limit; ~70 mmHg) and myogenic vasoconstriction (upper limit; ~160 mmHg): CBF remains relatively stable as MAP changes within this range. Perfusion decreases when MAP drops below the lower limit; however, overt symptoms are not observed until a critical perfusion threshold is reached, usually 40–60% below normal levels. The MAP range where perfusion drops without symptoms is termed the cerebrovascular reserve capacity. Hypoperfusion and ischemia occur at MAP levels below the reserve capacity; hyperperfusion and vasogenic edema occur at MAP levels above the upper limit. It must be stressed that the lower and upper limits of autoregulation, the size of the cerebrovascular reserve capacity and the level of perfusion maintained by autoregulation all display variation. Thus, the plot represents regularly quoted values.

Figure 2

Expected effects of subarachnoid hemorrhage on autoregulation. Altered vascular reactivity in subarachnoid hemorrhage (SAH) can have three hypothetical effects on cerebral autoregulation. Note that in this figure, cerebral autoregulation is plotted as the relationship between cerebral blood flow (CBF) and cerebral perfusion pressure (i.e., the difference between mean arterial pressure and intracranial pressure): this was done because intracranial pressure varies in SAH patients, thereby adding a variable to consider when relating CBF to mean arterial pressure in this pathological setting. The autoregulation curve in black represents the normal, non-pathological situation, while the red and yellow lines represent altered autoregulation. In (A), augmented myogenic reactivity (i.e., microvascular constriction) reduces perfusion, shifts the upper limit of autoregulation leftward and narrows the autoregulatory range. In severe cases, cerebral blood flow drops below the critical perfusion limit. In (B), upstream large artery constriction (i.e., angiographic vasospasm) reduces the perfusion pressure entering the microcirculation. This stimulates a right-ward shift in the autoregulatory curve, but perfusion deficits do not occur until the new lower limit is reached. In (C), both microvascular and larger artery constriction occur, creating a hybrid of (A) and (B).

Figure 3

Molecular mechanisms augmenting microvascular constriction in subarachnoid hemorrhage and potential interventions. A mechanosensitive complex initiates myogenic vasoconstriction via membrane potential depolarization: this leads to calcium entry via opening of voltage-gated calcium channels; voltage gated potassium channels also open, leading to hyperpolarizing potassium efflux that limits the extent of depolarization (negative feedback). Intracellular calcium activates calmodulin (CAM), myosin light chain kinase (MLCK) and the contraction apparatus. In addition, calcium entry and depolarization lead to the activation of sphingosine kinase 1 (Sphk1), which synthesizes and releases sphingosine-1-phosphate (S1P) into the extracellular compartment. Extracellular S1P activates the S1P2 receptor subtype (S1P₂R), thereby activating the Rho-associated protein kinase (ROCK) signaling pathway. ROCK signaling inhibits myosin light chain phosphatase (MLCP), which enhances MLCK's activation of the contractile apparatus. Extracellular S1P is sequestered from S1P₂R by the cystic fibrosis transmembrane conductance regulator (CFTR), which transports S1P across the plasma membrane for degradation. In subarachnoid hemorrhage (SAH), potassium channels are down-regulated, leading to enhanced depolarization through disinhibition. SAH also stimulates inflammatory tumor necrosis factor signaling, which down-regulates CFTR expression and enhances the activation of Sphk1. This increases pro-constrictive S1P / S1P₂R / ROCK signaling, which enhances constriction via the inhibition of MLCP. Therapeutics targeting these pathological processes include: (i) intra-arterially-delivered nimodipine (calcium channel blocker; limits calcium entry), (ii) retigabine (potassium channel activator; reduces depolarization), (iii) etanercept (inhibits TNF signaling; reduces S1P synthesis and increases S1P degradation), (iv) lumacaftor (increases CFTR expression; increases S1P degradation), (v) fingolimod (stimulates S1P receptor internalization; inhibits ROCK activation), and (vi) fasudil (ROCK inhibitor; limits inhibition of MLCP).