Action on the Cerebral Vascular Endothelium in the Prevention of Stroke

Abstract

Stroke or cerebrovascular accident (CVA) is a frequent, disabling pathology, consumes enormous social and health resources and has high morbidity and mortality. A large part of the resources of the health systems are allocated to the treatment of stroke, which is achieving better results every time, and far fewer resources are allocated to prevention. The objective of this review is to raise awareness in the different states so that they allocate more resources to prevention through awareness programs for health personnel, and implementation of detection tests for atherosclerotic cardiovascular disease in order to reduce the incidence of stroke. Clients should be insisted on adopting an adequate lifestyle, as well as acting on risk factors. Most strokes can be prevented through health education, blood pressure control, and lifestyle changes such as eating a healthy diet, being physically active, and stopping smoking.

1. Introduction

Atherosclerotic cardiovascular disease (ACVD) is a chronic, generalized, and progressive pathology that modifies the arteries until it causes a cardiovascular event. Elevated low-density lipoproteins (LDL-C) in plasma over time is one of the main causes of this disease, along with other risk factors. Cardiovascular diseases are the leading cause of disability and death from middle ages of life in developed countries, in both sexes. Cerebrovascular disease (CVD) encompasses anatomoclinical entities caused by reduced blood supply in a certain vascular territory (ischemic-type CVD) or by rupture of an intracranial vessel (hemorrhagic-type CVD) [1].

One in six people in the world will suffer a stroke, representing the third cause of death in the West, being the first in women. In Europe, 1.3 million people suffer a stroke each year and it is the second most frequent cause of death. With about 25 million cases per year, acute ischemic stroke represents a major public health challenge worldwide [2, 3]. Strokes have increased globally in absolute terms, as well as associated deaths, partly due to the greater number of cases registered in low- and middle-income countries as well as the aging of the population [4]. In total, 90% of stroke cases can be correlated with behavioral factors, including poor diet, smoking, and little physical activity, as well as metabolic factors such as obesity, hypertension, and diabetes mellitus [5].

The four main noncommunicable diseases (NCDs), such as cardiovascular disease (including stroke), cancer, type 2 diabetes mellitus (DM2), and lung disease, share 4 risk factors: tobacco use, unhealthy diet, physical inactivity, and alcohol abuse. Therefore, from a public health perspective, mass actions on lifestyle factors are the most cost-effective means of NCD prevention [6]. In recent years, several studies have reported that alterations in the gut microbiota (GM) could be a risk factor for stroke [7, 8]. Vascular endothelial dysfunction (VED) presents with a loss of balance between the vasodilation and vasoconstriction factors derived from it, with a predominance of the latter, producing progressive pathophysiological changes that make it possible to cause proinflammatory, prooxidant, proliferative, and procoagulant effects and vascular adhesion, contributing to atherogenesis in each of its phases [9].

The prevention of ACVD in high-risk patients is one of the main challenges that healthcare professionals face in order to reduce the rates of morbidity and mortality from stroke.

Primary prevention refers to the adoption of a healthy lifestyle from an early age and secondary prevention refers to the implementation of measures aimed at acting on cardiovascular risk factors (CVRF).

2. Causal factors

Ischemic infarcts are produced by the acute occlusion of one of the large cervical or cerebral arteries, either by a gradual narrowing of atherosclerotic origin or by a sudden occlusion produced by a thrombus (if it originates from the same cerebral arterial system) or an embolus (if the clot originates in a region of the vascular system other than the brain). In the case of hemorrhagic stroke, the rupture of a blood vessel occurs either at the intracerebral level (intracerebral hemorrhage) or by the rupture of aneurysms at the bifurcation of the great arteries on the surface of the brain (subarachnoid hemorrhage). Most strokes are ischemic (85%) and 15% hemorrhagic. A total of 15% of strokes occur in children [10, 11]. A small percentage of ACVD is related to genes [12].

Different studies demonstrated an association between elevated levels of total cholesterol and LDL-C and increased risk of ischemic stroke [13, 14]. A high intake of sugars, including added sugars and those naturally present in honey and fruit juices, is associated with an increased risk of developing cardiovascular diseases and, specifically, stroke [15]. In recent years, several studies have linked stroke with gut dysbiosis (GD) [16]. Although there are many causes of stroke, this chapter focuses on the prevention of ischemic strokes as they are the most frequent.

3. Ischemic stroke risk factors

Most strokes are due to modifiable risk factors, so there is a possibility of prevention. The main non-modifiable risk factor for stroke is age. In one-third of strokes, the cause is unknown [17].

Table 1 contains the most frequent modifiable risk factors according to O’Donnell et al., [18], updated by the authors.

Potentials	Established
Obesity/overweight	High blood pressure
Sedentary lifestyle	Diabetes mellitus
Glucose intolerance	Carotid stenosis
Malnutrition	Atrial fibrillation
Excessive alcohol intake	Previous ischemic heart disease
Smoking	Smoking
Blood hypercoagulable states	Sickle cell anemia
Hyperhomocysteinemia
Drug addiction (cocaine, etc.)
Use of oral contraceptives/Hormone replacement therapy
Inflammatory processes
Obstructive sleep apnea
Intestinal dysbiosis, alteration of the intestinal barrier, and neuroinflammation

Table 1.

Modifiable risk factors in stroke prevention according to O’Donnell et al., 2016 [18], updated by the authors.

Arterial hypertension (AHT) is the main risk factor involved in cerebrovascular disease, both in ischemic and hemorrhagic strokes. GD has been observed in the prehypertensive state compared to a normotensive population. These changes precede the development of AHT and are not due to AHT itself [19]. Obesity increases the risk of suffering a stroke, especially abdominal fat. It is a public health problem because it is related to many diseases, among others, hypertension and DM2. Furthermore, the number of cases has increased greatly in recent years and has become an epidemic [20]. A sedentary lifestyle, as a cardiometabolic risk factor, contributes to the appearance of a stroke [21]. The cardiovascular risk in patients with obesity and DM2 is increased since it is generally accompanied by other cardiovascular risk factors such as AHT, hypercholesterolemia, hypertriglyceridemia, and metabolic syndrome (MS) among others [22, 23]. For several decades, numerous studies have linked the act of smoking with an increased risk of stroke. The related components are attributed to nicotine, oxidizing gases, and carbon monoxide. This risk also exists in passive smokers [24]. According to the 2016 Interstroke study, high and moderate alcohol intake is associated with an increased chance of suffering a stroke [18]. Prediabetes and DM2 are associated with increased vascular risk in parallel with the degree of hyperglycemia and the lack of good metabolic control. In patients with type 1 diabetes mellitus, the frequency of stroke is lower. Diabetics are at high risk of atherosclerosis and often have other atherogenic risk factors, such as AHT, hyperlipidemia, and obesity, known as MS [25]. The role of dyslipidemias, especially the elevation of total serum cholesterol, as well as LDL-C is a known factor in CVD that contributes to ischemic stroke [13, 14]. Established AHT is one of the most prevalent modifiable risk factors, being associated with more severe strokes and with a worse prognosis [26]. The causal relationship between GM and AHT is more evident when studying AHT secondary to obstructive sleep apnea syndrome [27]. The presence of a coagulopathy is a potential risk factor for a cardiovascular event, but another independent risk factor is necessary, which acts by another mechanism to predispose to strokes, such as taking oral contraceptives, homocystinuria, etc. [28].

Associated with the aging process, there is a loss in the integrity of the intestinal epithelial barrier, a decrease in the number of enteric neurons and an increase in the synthesis of proinflammatory cytokines [29], factors possibly involved in the higher incidence of stroke from the average age of life.

4. Role of the microbiota-gut-brain axis in cerebrovascular disease

In the intestine, a series of products are generated by GM that exert their influence on the central nervous system (CNS), such as short-chain fatty acids (SCFAs), secondary bile acids, or tryptophan metabolites, which exert their function through ascending signals that start locally, either by crossing the intestinal barrier to pass into the systemic circulation or even acting directly in the CNS by crossing the blood-brain barrier [30]. Microbial products that reach systemic circulation are capable of modulating the immune system toward a more inflammatory environment or inducing tolerance, both locally and in the CNS. A central role in this modulation is exerted through the products generated by the metabolism of dietary components, such as dietary fiber, tryptophan, or arginine, which give rise to polyamines, indoles, and SCFA, which are capable of increasing the expansion of regulatory T lymphocytes, favoring an antiinflammatory phenotype in dendritic cells and decreasing the production of proinflammatory cytokines in neutrophils and macrophages. Another mechanism that GM also uses to regulate the immune response is the modification of the host’s own metabolites, in the case of secondary bile acids that regulate dendritic cells, macrophages, and natural killer cells, or through metabolites produced by intestinal bacteria, such as polysaccharide A from Bacteroides fragilis, with an antiinflammatory effect, or those produced by segmented filamentous bacteria, with a proinflammatory effect [31]. On the other hand, a correlation has been found between the increased risk of stroke and a greater burden of opportunistic pathogens, together with low levels of butyrate-producing intestinal bacteria [32]. Recent studies in animal models and later in human fecal samples after suffering an ischemic stroke compared to a control group have linked a certain GM with a higher risk of suffering a stroke, so it would become a modifiable risk factor [33]. Currently, the actions of microorganisms are beginning to be assessed as risk factors, such as infections caused by Chlamydia pneumoniae and Helicobacter pylori, reactivation of the varicella-zoster virus, etc. [34].

Within the actions of the microbiota-gut-brain axis (MGBA), through the vagus nerve, different microbial metabolites are detected and are capable of generating responses at the central level, as well as producing cholinergic responses secondary to peripheral inflammation, which translate into alterations in intestinal permeability and modulation of GM composition [35]. Among the environmental factors that increase intestinal permeability are alcohol consumption, prolonged use of antibiotics, abuse of non-steroidal antiinflammatory drugs, food allergies, radiation, and chemotherapy. Another group is made up of artificial sweeteners, such as aspartame and sucralose, pesticides, some household detergents, environmental pollutants, gluten in celiac patients, and the consumption of some marine fish that concentrate heavy metals [36, 37]. Under certain circumstances, GM can become unbalanced and favor the expansion of pathobiont microorganisms, organisms of the GM that are harmless under normal conditions but with infectious capacity in certain states [38], which can alter the entire host immune response and increase permeability of bowel [37]. Large uncharged molecules, such as proteins or lipopolysaccharides, or large charged molecules can pass through the tight junctions between epithelial cells [39]. However, deregulation of these junctions as a result of genetic or environmental factors, such as diet, drug use, or the activity of pathogenic microorganisms, can cause increased intestinal permeability. This phenomenon is frequently observed in inflammatory bowel diseases and in some metabolic diseases, such as diabetes or obesity [40]. In murine models, it has been observed that GM is a factor that can significantly influence the genesis of stroke [41]. SCFAs are an important class of bacterial metabolites that are obtained from the fermentation of polysaccharides (fibers) [42]. Preliminary studies showed that SCFAs have an important role in maintaining intestinal integrity and have an antiinflammatory effect [43]. One of the SCFAs, butyrate, is a preferential energy source for intestinal epithelial cells, thus contributing to their physiology [44]. SCFAs can reach the brain, due to the presence of transporters of these molecules in the endothelial cells of the blood-brain barrier [45]. Once there, they can modulate neuroinflammation by acting on the morphology and activation of microglia in the event of stroke [45].

GM can generate potentially toxic compounds, such as the formation of trimethylamine from choline and carnitine present in the diet [46]. Trimethylamine is absorbed and transformed into trimethylamine N-oxide (TMAO) in the liver, being considered a risk factor for cardiovascular disease [47].

These mechanisms may partly explain the factors dependent on the human microbiome that may favor stroke.

5. Role of the vascular endothelium

Endothelial cells (ECs) are capable of detecting physical changes related to mechanical stress caused by blood flow, blood pressure, or wall distension. When an imbalance occurs in the bioavailability of vasoactive substances, the predisposition to platelet aggregation, thrombosis, inflammation, vasoconstriction, or increased vascular permeability, a situation called vascular endothelial dysfunction (VED), occur.

VED is one of the initial events of atherosclerosis, it plays a fundamental role in ACVD and, therefore, in CVD [48]. GM has the ability to produce metabolites that directly affect the host’s cardiovascular system, being able to generate antagonistic effects (pro- and antiinflammatory, vasodilator, and vasoconstrictor) with both beneficial and harmful results. These metabolites include SCFA, TMAO, nitrites, indoles, and hydrogen sulfide. In AHT models, it has been shown that there is a decrease in the intestinal bacterial populations that produce SCFA and hydrogen sulfide (both with vasodilator properties). At the other extreme, TMAO-type metabolites, as well as indoles, would favor arterial vasoconstriction [49]. In experimental animals, it has been possible to induce atherosclerotic lesions similar to those found in human arteries, through the administration of diets rich in cholesterol and saturated fat. This type of diet produces an increase in plasma LDL-C concentrations and facilitates its accumulation in the subendothelial space in areas where permeability is increased. In these models, it has been observed that the regions most prone to developing atherosclerotic lesions present a greater permeability to LDL-C and very low-density lipoproteins (VLDL) [50]. It has been observed that high concentrations of native LDL-C and low concentrations of oxidized LDL-C increase vascular permeability since they reduce the content of heparan sulfate proteoglycans in the extracellular matrix of the subendothelial space. This effect would be produced by a negative regulation of the synthesis of these molecules, as well as an increase in their degradation thanks to the induction of endothelial secretion of heparanase [51].

VED is characterized by an imbalance between the relaxation and contraction factors derived from the endothelium [52] and is both the cause and effect of atherosclerotic lesions in cerebral arteries [53]. In SARS-Cov-2 infection, thrombotic complications are frequent and severe. Loss of even a small number of endothelial cells due to infection could lead to a breakdown of the endothelial barrier, resulting in “vascular leakage,” thus exposing inflammatory cells. This would lead to an abnormal activation of the coagulation system that would cause inflammation of small vessels and microthrombi, which could affect the heart, lungs, or brain [54].

Numerous factors and markers of endothelial damage have been studied, which turn out to be predictors of an advance in the development of atherosclerotic plaque and, therefore, of its instability. The quantification of the degree of vasodilation mediated by hyperflow (VMH) of the brachial artery is a noninvasive, cheap, simple, reproducible, readily available, and validated ultrasonographic technique that allows us to know the state of health and function of the vascular endothelium. It is a response dependent on endothelial nitric oxide and, when it is decreased, translates to a VED. VMH is reduced in patients with vascular risk factors, cerebral, coronary, or peripheral vascular disease, and is an independent predictor of vascular events and vascular recurrence. It also allows us to be able to detect and quantify the degree of VED early, anticipating the appearance of atheromatous plaque. VED improves with various drugs, such as antihypertensives, antidiabetics, antiaggregants, or lipid-lowering agents [55].

6. Precautionary measures

Stroke is a disease that, to a large extent, can be avoided. Therefore, identifying the risk factors of each person is key to drawing up a preventive strategy at the individual level. The scope of action to carry out these activities is primary health care. A healthy lifestyle can reduce the risk of cardiovascular events. Most strokes can be prevented with hygienic-dietary habits. For this, modifiable risk factors must be monitored, such as obesity/overweight, sedentary lifestyle, smoking, alcohol abuse, AHT, dyslipidemia, DM2, and previous heart disease. There are cardiovascular risk factors that cannot be modified, such as age, sex, family history, thrombophilia, and previous strokes. It is necessary to carry out awareness campaigns on stroke in preventive aspects. Table 2 contains the recommendations of the Diabetes and Cardiovascular Disease Working Group of the Spanish Diabetes Society (SED, 2014–2015) [22].

Aspects to consider	Recommendations	Intervention
Mediterranean diet	Diet with a predominance of plant-based foods	Celiacs, food allergies, and intolerances
Physical exercise	Aerobic, 150 minutes a week, 3 days minimum with moderate intensity.	Adaptations according to particular situation
Quitting the smoking habit	Collect in the medical history the beginning, frequency of consumption, if you inhale smoke, etc.	Choosing the most appropriate smoking cessation method
Overweight/obesity	Progressive weight loss until reaching ideal weight	BMI >35 + DM2: bariatric surgery
Glycemic control	Hb1c < 7	Hb1c >8 + CVFR, DM2, elderly, complications, etc.
Lipids	LDL-C < 100 mg/dl (Primary prevention); LDL-C < 70 mg/dl (secondary prevention)	Diet + physical exercise; Statins etc.
Blood pressure	< 140/90 mmHg; low salt diet	In case of nephropathy: Angiotensin-converting enzyme inhibitors, etc.
Blood coagulation status	Primary and secondary prevention	Acetylsalicylic acid: 100 mg/day in case of CVFR
Vitamins	Vitamin D > 30 ng/ml; Vitamin B12 > 160 pg./ml	Supplement with levels <20 ng/ml; Supplement in case of prescription of metformin, vegan diet

Table 2.

Recommendations of the diabetes and cardiovascular disease working group (SED, 2014–2015), adapted by the authors of the chapter.

Eating a healthy diet, rich in plant-based foods, can help modify IM so that the production of deleterious metabolites such as TMAO is reduced [56]. Plant-based diets are associated with significant benefits in the improvement or prevention of metabolic diseases (overweight, obesity, DM2), cardiovascular disease, inflammatory bowel disease, and chronic kidney disease. In addition, a very important emerging aspect, in which the evidence is growing, is the beneficial effect on aging and aspects linked to it, such as sarcopenia [57, 58]. Proteins, carbohydrates, and fats present in plant foods can shift the GM profile toward increased production of antiinflammatory compounds and decreased production of endogenous toxins. Vegetable fats, particularly olive oil, are antiinflammatory and antiatherogenic [21].

Moderate-intensity physical exercise, such as walking or cycling, should be part of daily activity in healthy adults [59, 60]. Keeping your weight within healthy limits is very important for the normal functioning of the heart, blood vessels, metabolism, bones, and other organs. All this happens to maintain a balance between the calories that are ingested. A balanced diet, physical exercise, and in some cases drugs can help achieve this goal. Glycemic control, especially in predisposed patients, is an important factor in order to prevent the complications of DM2. Various antidiabetic drugs may play an important role in stroke prevention [61]. The management of dyslipidemias is based on implementing healthy lifestyle habits and pharmacological treatment. The indication to start lipid-lowering treatment will depend on the vascular risk of each subject. Statins are the drugs of choice. Other effective lipid-lowering agents are ezetimibe combined with statins and PCSK9 (protein convertase subtilisin-kexin type 9) inhibitors. Other drugs such as fibrates or omega-3 fatty acids are useful in the management of triglycerides, although their usefulness in the prevention of vascular diseases is not well defined [62, 63]. Reducing blood pressure is the key, both in the primary prevention of the disease and in the secondary to avoid its recurrence. It is recommended to start antihypertensive treatment for primary prevention of stroke in patients with blood pressure figures higher than 140/90 mmHg [26]. Anticoagulants are recommended in case of atrial fibrillation in any patient over 75 years of age and with several CVRFs [64].

In stroke prevention campaigns, emphasis must be placed on the importance of rapid action in the event of a stroke. Hospitals have protocols (stroke code) for early diagnosis with imaging tests using artificial intelligence and early treatment in order to minimize neurological damage. Having suffered a stroke is a risk factor for suffering it again. For this reason, secondary prevention, the adoption of good lifestyle habits, and good adherence to prescribed treatments are essential [65]. Once the sequelae of the stroke have been assessed early, both physical (speech therapy and physiotherapy) as well as social and psychological rehabilitation begins after 48–72 hours. The idea is to go to a neurorehabilitation unit. The objective is for the patient to remain independent and autonomous for the basic and instrumented activities of daily life. Between 40 and 50% of patients abandon treatment 2 or 3 years after having suffered a stroke, which favors the appearance of a second event, the repercussion of which will be worse than that of the first [66]. Biomarkers that predict stroke outcome include serum triglyceride level, HDL-cholesterol [67], interleukin-6 (IL-6), NT-proBNP [68], and YKL-40 [69]. IM modulation, especially with prebiotics and/or probiotics, represents a preventive and therapeutic approach to take into account in the approach to ACVD [70].

7. Conclusions

1. The adoption of a lifestyle based on a diet with a predominance of foods of vegetable origin and the performance of physical exercise adapted according to age is the basis for the prevention of atherosclerotic cardiovascular disease.

2. In primary prevention, it is recommended to determine the patient’s vascular risk in order to define the appropriate LDL-C figure.

3. In secondary prevention after a stroke of atherothrombotic origin, LDL-C levels of less than 55 mg/dl are recommended, while in ischemic strokes of nonatherothrombotic origin, the objectives will be established based on the vascular risk group of each patient.

4. Both in primary and secondary prevention, statins are the drugs of first choice in dyslipidemia, and ezetimibe and/or PCSK9 inhibitors can be associated in those cases that do not reach the therapeutic objectives.

5. In the near future, we will be able to prevent strokes or improve neurological recovery through intervention in the gut microbiota.

Acknowledgments

The chapter has been funded by the Institute for Integrative Medicine.

Conflict of interest

There is no conflict of interest.

Abbreviations

CVA	cerebrovascular accident or stroke
ACVD	atherosclerotic cardiovascular disease
CVD	cerebrovascular disease
NCD	noncommunicable diseases
DM 2	type 2 diabetes mellitus
GM	gut microbiota
VED	vascular endothelial dysfunction
CVRF	cardiovascular risk factors
LDL-C	low-density lipoproteins
GD	gut dysbiosis
AHT	arterial hypertension
MS	metabolic syndrome
CNS	central nervous system
SCFAs	short chain fatty acids
MGBA	microbiota-gut-brain axis
EC	endothelial cells
TMAO	trimethylamine oxide
VLDL	very low-density lipoproteins
VMH	quantification of the degree of vasodilatation mediated by hyperflow
IL-6	interleukin 6