From Hypertension to Stroke: Mechanisms and Potential Prevention Strategies

SUMMARY

Stroke is a major cause of disability and death worldwide. Prevention aimed at risk factors of stroke is the most effective strategy to curb the stroke pandemic. Hypertension is one of the most important risk factors for stroke. Despite the substantial evidence of the benefits of lowering blood pressure, conventional treatment does not normalize the burden of major cardiovascular events in patients with hypertension. Fully understanding the factors involved in the hypertension‐induced stroke helps to develop new strategies for stroke prevention. Antihypertensive therapies selected should have positive blood pressure‐independent effects on stroke risk. This review summarizes the factors involved in the hypertension‐induced stroke, such as oxidative stress, inflammation, and arterial baroreflex dysfunction, and potential strategies for its prevention, therefore, provides clues for clinicians.

Introduction

Stroke is the primary cause of adult disability and presents a serious and growing threat to public health [1]. According to World Health Organization figures for 2008, stroke has been the second leading cause of death in the world, with its proportion from 9.7% in 2004 to 12.1% in 2030 [2]. Ischemic stroke was the most frequently occurring type of stroke, accounting for ∼70% of all stroke events in China and 80–85% in Western countries [3, 4].

Apart from death, the greatest burden of stroke on health care system, is cost of care for long‐term physical and mental disability [1, 5]. Approximately one‐third of stroke victims die within 1 year, and an equal number of patients are permanently disabled. Strategies to reduce the incidence of stroke include prevention of stroke and treatment of patients with acute stroke to reduce death and disability. However, once an attack has occurred, effective treatments are limited; thus, prevention is considered the most effective strategy to curb the stroke pandemic [6].

Risk factors for stroke are well identified [7, 8] and can be classified into (1) nonmodifiable: age, sex, race, various genetic factors, etc; (2) modifiable: hypertension, diabetes, hyperlipidemia, atrial fibrillation, smoking, obesity, etc [9, 10, 11, 12, 13]; (3) potentially modifiable: alcohol or drug abuse, oral contraceptive use, infection, the metabolic syndrome, etc. The goal of stroke prevention is to identify high‐risk patients and to target the modifiable risk factors through the use of appropriate pharmacologic and nonpharmacologic interventions. Hypertension is the most powerful modifiable factor and the second most powerful risk factor, after age, for stroke [14], regardless of geographic location and ethnicity. Approximately 54% of strokes worldwide can be attributed to hypertension [15]. People with hypertension are 3 to 4 times more likely to suffer a stroke than those without hypertension [16].

Mechanisms Involved in the Pathogenesis of Hypertension‐Induced Stroke

There is a delay between the onset of hypertension and a hypertensive complication. During this long period, a series of changes take place in the cardiovascular system including cerebral circulation. These changes, such as vascular remodeling, inflammation, oxidative stress and baroreflex dysfunction, etc., may contribute to the pathogenesis of stroke in hypertension.

Alterations in the Structure of Cerebral Blood Vessels

Hypertension has profound effects on the structure of cerebral blood vessels. Mechanical, neural, and humoral factors all contribute to the changes in composition and structure of the cerebrovascular wall. Hypertension promotes the development of atherosclerotic plaques in cerebral arteries and arterioles, which may lead to arterial occlusions and ischemic injury [17, 18, 19]. In addition, hypertension induces lipohyalinosis of penetrating arteries and arterioles supplying the white matter, resulting in small white matter infarcts or brain hemorrhage [18].

Hypertension induces hypertrophy and remodeling of smooth muscle cells in systemic and cerebral arteries, both of which are aimed at reducing stress on the vessel wall and protecting downstream microvessels [20, 21]. Under a chronic high intraluminal pressure, smooth muscle cells undergo hypertrophy, hyperplasia, or rearrangement and grow inward encroaching into the lumen of the artery, resulting in narrowing of the vessel lumen, with increase in the wall thickness or not. Hypertension also leads to vascular stiffening, resulting in increase in pulse pressure, a good predictor of stroke [21, 22]. Factors contributing to hypertrophy in cerebral arteries and arterioles include sympathetic perivascular innervation [23] and mechanical effects of the elevated intraluminal pressure on the vascular wall, mediated by growth factors, oxidative stress and NO [24, 25]. Angiotensin II (Ang II) is a key factor in the mechanisms of cerebrovascular remodeling, with reactive oxygen species (ROS) involved in it [26]. ROS promote smooth muscle cell proliferation and initiate remodeling of the extracellular matrix via activation of matrix metalloproteases [27]. Extracellular matrix proteins, as well as integrin ανβ3, emilin‐1, and elastin‐1 [28, 29, 30], play a critical role in hypertrophy, remodeling, and stiffening. Cerebral arterioles undergoing hypertrophy or remodeling have reduced stiffening [31]. However, changes in cerebrovascular wall composition caused by sustained hypertension may lead to stiffening [32]. Therefore, duration and magnitude of the blood pressure (BP) elevation, as well as vessel size are all important for the alteration in the cerebrovascular wall induced by hypertension.

Alterations in Cerebral Blood Flow in Hypertension

Recent studies have shown reductions in cerebral blood flow (CBF) in selected brain regions [33], which may precede cerebrovascular symptoms or white matter lesions [34]. The enhancement of CBF induced by brain activation is decreased in hypertensives [35], representing attenuated functional hyperemia accompanying hypertension. Hypertension alters endothelium‐dependent relaxation of cerebral blood vessels. The increase in CBF caused by endothelium‐dependent vasodilators is attenuated in hypertensive rats [36]. Furthermore, the CBF reduction, accompanying hypertension, might be the result of increased vascular tone secondary to endothelial dysfunction [37]. Endothelial dysfunction also results in overproduction of NO, which may increase the permeability of cerebral vessels, resulting in cerebral edema.

Cerebrovascular autoregulation renders CBF independent of changes in arterial pressure within a certain range (60–150 mmHg mean arterial pressure), and has myogenic and neurogenic components. Experimental and clinical studies have demonstrated that hypertension leads to a shift of the cerebrovascular autoregulation curve to the right towards higher‐pressure values [38]. Increased myogenic tone, remodeling and hypertrophy occurring in hypertension contribute to the shift in autoregulation by reducing the vascular lumen and increasing cerebrovascular resistance [21, 37, 39]. In addition, endothelial dysfunction might also attenuate or abolish myogenic autoregulation. Consequently, higher perfusion pressures are needed to maintain the adequate CBF in hypertension to prevent cerebral hypoperfusion, which may be caused by excessive antihypertensive medication. In hypertension, intracranial arterial vasculature is dilated, thus resulting in weakened ability for additional vasodilatation in response to ischemic events and a higher risk for subsequent accidents.

Oxidative Stress

Oxidative stress is a condition in which generation of ROS exceeds the capacity of the antioxidant defense system. Either excess generation of ROS, depressed antioxidant capacity, or a combination of both can result in oxidative stress. Persistent oxidative stress can deplete antioxidant molecules, inactivate antioxidant enzymes, and thereby impair antioxidant defense system [40, 41].

There is compelling evidence that oxidative stress play a critical part in the pathogenesis of hypertension, and stroke as a long‐term complication [42, 43]. Oxidative stress in the cerebral blood vessels and brain can cause hypertension, based on the evidence that induction of oxidative stress causes hypertension in normal animals [44]. ROS is a major mediator of the cerebrovascular dysfunction induced by Ang II, via activation of NADPH oxidase, in vasculature [45]. The enzyme NADPH oxidase is the main source of ROS mediating cerebrovascular dysfunction [46], and upregulation of NADPH oxidase has been demonstrated in various models of hypertension [47, 48]. ROS production within BP control regions of brain contributes to the neurohumoral changes that drive the hypertension [49]. Peroxynitrite is the product of the reaction between NO and the radical superoxide. It can induce DNA damage and lipid peroxidation, change protein function [50]. Peroxynitrite exerts deleterious effects on cerebral blood vessels [51], which can account for the cerebrovascular dysfunction induced by Ang II.

In addition, hypertension itself can result in oxidative stress in cerebral blood vessels. This concept is based on the evidence that ROS production in cerebral vessels is increased in Ang II‐induced hypertension [52, 53]. Free radical scavengers could curb the effects of hypertension on functional hyperemia and endothelium dependent responses, indicating that the cerebrovascular dysfunction is mediated by ROS. Therefore, oxidative stress participates in the structural and functional alterations of cerebral blood vessels induced by hypertension.

Inflammation in Hypertension

Inflammation is a vital process that leads to changes in vascular wall integrity, and emerges as a common pathological mechanism in a variety of vascular diseases, including atherosclerosis and cerebral aneurysms [54, 55]. Studies have shown that the biomarkers of inflammation can predict risk of primary ischemic stroke [56]. Inflammatory markers such as C‐reactive protein (CRP), interleukin‐6 (IL‐6), leukocyte elastase, lipoprotein (a), intercellular adhesion molecule‐1 (ICAM‐1), and E‐selectin are consistently higher in people prone to develop stroke compared with those who are not. Inflammation may also lead to a worse outcome following stroke, resulting from the increase of CRP in response to IL‐6 [57, 58]. Additionally, inflammation per se has been identified as a “novel” risk factor for stroke [6, 59, 60].

There is increasing evidence supporting the role of vascular inflammation in the pathogenesis of hypertension [43, 61]. Activation of circulating leukocytes has been observed in hypertensive humans and animals [62, 63]. The causal role of inflammation in the pathogenesis of hypertension is further supported by the observation that reducing or blocking inflammation leads to amelioration of hypertension [64, 65]. In addition, hypertension‐induced oxidative stress stimulates inflammatory reactions in cerebral blood vessels, as a result of production of chemokines, cytokines, and adhesion molecules and proliferation of lymphocytes. Conversely, inflammation causes oxidative stress, since activated immune cells have been shown to produce ROS and express Ang II, resulting in oxidative stress and hypertension [66]. Thus, oxidative stress, inflammation, and hypertension are involved in a self‐perpetuating vicious cycle, if without proper treatment, culminating in stoke as a frequent outcome.

Arterial Baroreflex Dysfunction in Hypertension

Arterial baroreflex is one of the most important physiological mechanisms controlling BP regulation [67]. Recently, much interest has been focused on the pathological significance of arterial baroreflex dysfunction. Baroreflex sensitivity (BRS), a marker of arterial baroreflex function, was found as an important determinant in many cardiovascular diseases [68, 69]. We have reported that arterial baroreflex function plays an important role in the pathogenesis and prognosis of atherosclerosis, aconitine‐induced arrhythmia and LPS‐induced shock in animals [70, 71, 72].

Baroreflex can be less sensitive to any given change in BP with hypertension, due to changes in vascular distensibility and altered activity in the brainstem portion of the reflex [73]. Reduced BRS results in vascular changes, arterial stiffness, contributing to a vicious cycle of hypertension and related complications. Baroreflex impairment has been repeatedly shown to be present in acute ischemic and hemorrhagic stroke [74, 75]. Not only hypertension but also arterial baroreflex dysfunction accompanying it, is an important determinant of stroke [76]. Baroreflex dysfunction and BP variability may significantly alter cerebral perfusion and boost perihematomal edema after ischemic or hemorrhagic stroke [77, 78]. In addition, baroreflex dysfunction significantly increases the levels of the interleukin‐1 and IL‐6, as well as infarct volume [79]. It has been shown that baroreflex impairment is independently related to outcomes after acute ischemic stroke [80] or after intracerebral hemorrhage [75]. In patients, BP variability within short period (3–72 hours) after acute ischemic stroke is associated with an increased risk of poor outcome [81, 82]. Stroke is significantly delayed in rats with high BRS than those with low BRS (time to 50% death was 1.47‐fold longer than low BRS group, P < 0.01). Moreover, restoration of BRS by ketanserin can prevent stroke significantly in SHR‐SP, whether BP was reduced or not [76].

We have recently found that both expression and function of α7 subunit of nicotinic acetylcholine (ACh) receptor (α7‐nAChR) decreased in aorta of hypertensive rats; hypertension‐induced end‐organ damage (EOD) was more severe in α7‐nAChR^−/− mice than wild controls; administration of α7‐nAChR agonist may lessen EOD induced by hypertension. As to the determinant effect of arterial baroreflex on stroke, it might be explained by these observations: arterial baroreflex dysfunction induces a decrease in vagal tone; therefore, ACh secreted by vagus declined; thus, antiinflammatory effect of ACh mediated by α7‐nAChR attenuated as a result, which not only promotes the ictus but also worsens the outcome of stroke.

Taken together, there is an intercausal relationship among oxidative stress, inflammation, baroreflex dysfunction, and hypertension. If not interrupted, this vicious cycle might culminate in stroke, as a result of secondary morphological and functional alterations of cerebral blood vessels (Figure 1).

Figure 1.

Mechanisms by which hypertension induces stroke.

Strategies of Stroke Prevention in Patients with Hypertension

Hypertension is the most important modifiable risk factor for stroke. In most countries, up to 30% of adults suffer from hypertension [6]. Between 2000 and 2005, the prevalence of adult hypertension was predicted to have risen by 60%, and to affect a total of 1.56 billion people worldwide [83]. Moreover, about 54% of stroke was attributable to hypertension [15]. Thus, it is necessary to identify and treat hypertension and related vascular and neuronal dysfunction to prevent stroke.

Classic Strategies for BP Control

There is strong evidence that antihypertensive therapy is important for prevention of stroke, regardless of age, gender, or ethnicity [84, 85, 86, 87]. A meta‐analysis of nine randomized comparative trials found that a reduction in systolic BP of just 1 to 3 mmHg led to a reduction in risk of stroke of 20–30%[88]. However, discontinuation with antihypertensive therapy was associated with a 28% increase in the risk of stroke [89].

Several categories of antihypertensive drugs, such as thiazide diuretics, angiotensin‐converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β‐adrenergic receptor blockers, and calcium channel blockers (CCBs), reduce the risk of stroke in hypertensives [90, 91, 92, 93, 94, 95, 96], among which CCBs and ARBs have particularly strong supportive data for a protective effect against stroke [97, 98]. A meta‐analysis of two trials provided clear evidence of a reduction of 39% in stroke risk with CCBs versus placebo [99]. CCBs have also been shown to provide better protection against stroke than older drugs, such as β‐blockers and diuretics [100]. Candesartan‐based treatment of hypertension reduced nonfatal stroke by 27.8% and all stroke by 23.6% compared with placebo [101]. Compared with older drugs, treatment with ARBs lessened the incidence of stroke by 26%[102]. There is no difference in potential to prevent stroke between CCBs and ARBs [103]. In addition to lowering BP, there are BP‐independent components that contribute to the benefit of CCBs and ARBs on stroke [104]. Possible mechanisms for this additional benefit include: reductions in carotid intima‐media thickness, left ventricular mass or central BP, and improvement in CBF autoregulation [105, 106, 107], some of which are mediated by improvement in nitric oxide production, decrease in oxidative stress [108], and reduction of inflammation in cerebral microvessels [109]. Thus, single administration of these agents or combinations of multiple agents might optimize the cerebrovascular benefits of antihypertensive treatment for stroke prevention.

Reducing Oxidative Stress in Hypertension

Theoretically, oxidative stress in hypertension might be corrected by administration of antioxidants. However, mere administration of high doses of several antioxidant compounds such as ascorbic acid, beta carotene, and tocopherol, have shown no benefit or even increased the risk for stoke. It might be explained by the fact that oxidative stress in hypertension is not caused by deficiency of the given antioxidants, thus it cannot be corrected by administration of such agents. Moreover, traditional antioxidants are nonselective, which neutralize all free radicals including those essential for normal physiological activities. Thus, administration of supraphysiologic quantities of the traditional antioxidant compounds would lead to accumulation of their free radical metabolite, which can actually worsen oxidative stress. Therefore, consumption of high doses of these agents is not recommended for the prevention of stroke in hypertensive patients. Specific interventions directed at the specific underlying mechanism of oxidative stress in hypertension would be most effective [110]. Since Ang II promotes oxidative stress and hypertension, drugs that interrupt rennin‐angiotensin system (RAS) might be suitable for management of oxidative stress in certain types of hypertension [111]. As mentioned above, for example, CCBs and ARBs can not only lower BP but also decrease oxidative stress in hypertension. In addition, consumption of a diet rich in natural antioxidants and other essential micronutrients, as well as regular exercise and weight control, also helps to combat oxidative stress [112].

Recently, it has been reported that hydrogen may act as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals [113]. Ohsawa et al. showed that hydrogen selectively scavenge the toxic hydroxyl radical, through specifically quenching the hydroxyl radical while preserving other reactive oxygen and nitrogen species important in signaling. In rodents subjected to focal cerebral ischemia‐reperfusion, inhaled 2% hydrogen limited the infarct volume, if given before the reperfusion phase of injury. Most recently, inhalation of hydrogen, as well as injection of hydrogen saline has been proved to have antioxidant and antiapoptotic properties that afford neuroprotection in neonatal hypoxia–ischemia rat models [114, 115]. Moreover, hydrogen has been proved to possess antiinflammatory property, which is also mediated by neutralizing of hydroxyl radical [116]. Thus, we can expect that hydrogen might be a promising strategy for prevention of stroke in hypertensives.

Reducing Inflammation in Hypertension

It is well accepted that inflammation is an essential mechanism for EOD in hypertension. However, traditional antiinflammatory drugs could not be used for controlling inflammation and reducing organ damage in hypertension. Considering the proinflammatory effects of Ang II, antihypertensive approaches using agents affecting components of RAS, are beneficial because of their potential antiinflammatory properties [117, 118, 119]. It has been well know that ARBs such as telmisartan and olmesartan, exert antiinflammatory effect during antihypertensive treatment, by reducing levels of hsCRP, IL‐6, tumor necrosis factor‐α (TNF‐α) and monocyte chemotactic protein‐1 (MCP‐1) [120]. Furthermore, prestroke therapy with ACEIs appears to lessen stroke severity in patients [121]. ACEIs such as enalapril, have been found to reduce inflammatory process, through reduction of ICAM‐1, E‐selectin, and MCP‐1 [122, 123]. Captopril shows an antiatherosclerotic effect, and ramipril decreases inflammatory infiltrates in experimental models [124, 125]. Apart from angiotensin‐converting enzyme, chymase in mast cells is also involved in conversion of Ang I to Ang II. Chymase is considered to be responsible for >80% of tissue Ang II formation in the human heart and >60% of that in arteries [126]. Therefore, chymase has been implicated in the pathogenesis of cardiovascular diseases, including atherosclerosis and hypertension [127, 128]. Recently, it was reported that homocysteine may increase mast cell chymase expression and activity through the mechanism of oxidative stress [129, 130]. Indirect inhibition of chymase through inhibition of mast cell by ketotifen reduces splanchnic inflammatory response in a portal hypertension model in rats [131]. Furthermore, inhibition of chymase with Y‐40079 significantly abolished leukocyte rolling and adhesion in postischemic small intestine [132]. Thus, inhibitors of chymase might also be potential strategy for stroke prevention.

Moreover, statins such as rosuvastatin may reduce IL‐6 and TNF‐α in hypertensives [133]. Prestroke therapy with statins appears to lessen stroke severity [134, 135, 136] and cessation of prestroke statin therapy at the time of stroke appears deleterious [137]. Peroxisome proliferator‐activated receptor agonists such as pioglitazone, may also interfere with the inflammatory process in hypertension through reduction of CRP, ICAM‐1, and vascular cell adhesion molecule‐1 levels [138]. Recently, α7‐nAChR has been proved to be an essential regulator of inflammation [139], selective activation of α7‐nAChR inhibits inflammatory cytokine production in macrophages and monocytes, and in several models of inflammatory disease in vivo[140, 141, 142]. Therefore, selective agonists of α7‐nAChR may be considered to inhibit inflammation in hypertension.

Restoration of Impaired Arterial Baroreflex Function in Hypertension

Arterial baroreflex function can be positively influenced by certain drugs, especially β‐blockers [143]. A recent report showed that β‐blockers could lessen severity of stroke in ischemic stroke patients [144], and pretreatment with β‐blockers reduced infarct volume in experimental ischemia models [145]. It has been reported that β‐blockers can also reduce brain edema in either animals or patients with traumatic brain injury [146, 147]. However the benefit of β‐blockers in acute human stroke remains controversial [148, 149].

Ketanserin, a new type of antihypertensive drug, is a selective 5‐HT_2A receptor antagonist with additional α1‐adrenoceptor‐blocking properties. In our previous studies, it was found that ketanserin significantly improve BRS in hypertensive rats [150]. Ketanserin reduced the incidence of fatal strokes, through amelioration of BRS besides reduction of BP [76, 151]. Other drugs, such as clonidine, moxonidine, mecobalamin, and folic acid, also improved BRS [152, 153, 154, 155]. Baroreceptor stimulation has been used in patients with drug‐resistant hypertension [156]. It has been shown that vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia [157]. Therefore, baroreflex modulation through drugs or electrical stimulation might be a potential strategy for stroke prevention.

Conclusions

Stroke is a major public health concern, and hypertension is one of the most important risk factors. We have provided a brief overview of factors involved in the hypertension‐induced stroke and recent developments in its prevention. However, hypertension is often accompanied by many other systemic diseases, which also increase the risk for stroke. Combination treatment of these diseases besides hypertension‐related status, as well as a healthy life style may lead to more effective prevention of stroke.

Conflict of Interest

The authors have no conflict of interest.