Comorbidity of Anxiety and Hypertension: Common Risk Factors and Potential Mechanisms

Anxiety is more common in patients with hypertension, and these two conditions frequently coexist. Recently, more emphasis has been placed on determining etiology in patients with comorbid hypertension and anxiety. This review focuses on the common risk factors and potential mechanisms of comorbid hypertension and anxiety. Firstly, we analyze the common risk factors of comorbid hypertension and anxiety including age, smoking, alcohol abuse, obesity, lead, and traffic noise. The specific mechanisms underlying hypertension and anxiety were subsequently discussed, including interleukin (IL)-6 (IL-6), IL-17, reactive oxygen species (ROS), and gut dysbiosis. Increased IL-6, IL-17, and ROS accelerate the development of hypertension and anxiety. Gut dysbiosis leads to hypertension and anxiety by reducing short-chain fatty acids, vitamin D, and 5-hydroxytryptamine (5-HT), and increasing trimethylamine N-oxide (TAMO) and MYC. These shared risk factors and potential mechanisms may provide an effective strategy for treating and preventing hypertension and comorbid anxiety.


Introduction
Hypertension is the leading preventable risk factor for cardiovascular disease and all-cause mortality globally [1]. Te prevalence of hypertension projected to exceed 1.5 billion by 2025 [2]. Hypertension afects approximately 1 billion adults and associated with 9 million global fatalities annually [3]. Besides hypertension, mental disorders are serious public health concern [4]. According to a metaanalysis, the incidence of comorbid hypertension and anxiety is approximately 38% [5].
Anxiety disorders are the most common category of mental disorders. Te global prevalence of anxiety disorders is approximately 7.3%, accounting for 3.3% of the global disease [6]. Te World Health Organization ranked anxiety disorders as the ninth leading cause of disability due to their high prevalence, chronicity, and comorbidity [7]. Numerous studies have reported a positive association between hypertension and anxiety. Comorbidities, such as hypertension and anxiety are associated with lower treatment compliance, lower levels of daily functioning, lower healthrelated quality of life, and healthcare-related costs [8]. Furthermore, patients with hypertension are at a greater risk of cardiovascular disease-related mortality [9,10].
Here, we reviewed the relationship between hypertension and anxiety. Additionally, we discuss some of the most prevalent risk factors and potential mechanisms of comorbid hypertension and anxiety.

Positive Association between Hypertension and Anxiety
comprehensive and integrated interventions to reduce disability [11]. Te relationship between hypertension and anxiety is mutually reinforced. Longitudinal data and theoretical literature indicate that anxiety is an etiology for hypertension [12]. Anxiety is an independent risk factor of hypertension and promotes the development and progression of the condition. Patients with hypertension are prone to anxiety due to the disease or inefcacious treatment [13]. Anxiety disorders were more prevalent in patients with hypertension (37.9%) than in the general population (12.4%) [14]. Additionally, anxiety is an independent risk factor for hypertension [15] due to its infuence on unhealthy behaviors such as smoking, depression, a sedentary lifestyle, and being overweight [16]. Anxiety was more prevalent among older hypertensive patients with a medical history of stroke and depression [17]. Like essential hypertension, anxiety also consistently increases the risk of hypertensive disorders during pregnancy and eclampsia [18]. Accordingly, anxiety increases the probability of developing hypertension.
Until recently, research has suggested that older adults with comorbid hypertension and anxiety have an increased probability of medication noncompliance, resulting in decreased treatment efcacy [13]. Based on the preceding data, anxiety may be a barrier to medication adherence, exacerbating hypertension, and cardiovascular complications. Anxiety signifcantly afects the functional, cognitive, and afective dimensions of quality of life in patients with hypertension. Furthermore, individuals with hypertension incur an additional excess economic burden from anxiety [8]. Overall, anxiety is directly related to the life of patients with hypertension. Antianxiety treatment is efective in lowering blood pressure in hypertension patients [12]. Terefore, early detection and treatment of comorbid hypertension and anxiety are critical.

Risk Factors for Comorbid Hypertension and Anxiety
Te co-occurrence of hypertension and anxiety suggests the existence of mutual risk factors. Individual risk factors, lifestyle choices, and environmental risk factors (Table 1) are the primary risk factors associated with comorbid hypertension, according to a previous study. In this study, we analyzed the efects of these risk factors on the incidence of comorbid hypertension and anxiety.

Age.
Age is a specifc risk factor. Age was the most signifcant individual risk factor for comorbid hypertension related anxiety. Signifcant evidence indicates that the risk of hypertension increases with age [39]. Te prevalence of hypertension is 26% in people aged 20-44, compared to 78% among those >65 years of age [19]. Vascular endothelial cells (ECs) are widely known to play an important role in vascular homeostasis and tone modulation. With increasing age, ECs undergo vascular senescence, which exacerbates apoptosis and infammation, resulting in increased arterial stifness and loss of endothelial cell-induced vasodilation, thereby increasing the risk of hypertension [20]. Age enhances the severity of anxiety similar to hypertension [21]. Te fundamental cause could be that the number of 5hydroxytryptamine (5-HT) specifc receptors in the brain may be signifcantly reduced, increasing the probability of anxiety development [22]. 5-HT also promotes vasodilation by activating the 5-HT receptors in the endothelium to promote NO production. Tis implies that reducing 5-HT receptors may contribute to endothelial dysfunction [40]. Moreover, older adults with a higher prevalence of hypertension are more vulnerable to comorbid anxiety disorders [41]. Terefore, age is a primary risk factor for comorbid hypertension and anxiety.

Sex.
Sex also plays a role in the development of hypertension. Specifcally, reproductive hormones, such as estrogen and testosterone, likely contribute to sex diferences in blood pressure (BP) and anxiety [42]. Premenopausal women generally have benefcial metabolic, cardiovascular, and sympathetic profles under estrogen protective conditions [43]. However, the loss of estrogen due to menopause in women during midlife and older age could increase their susceptibility to "central obesity" and hypertension [23].
Similarly, women were twice as likely as men to experience anxiety [24]. Several lines of evidence indicate that "withdrawal" or decrease in estrogen during natural hormonal shifts (within the menstrual cycle, postpartum, and during the menopause transition) increases anxiety risk [25]. Terefore, understanding the sex diferences in cardiometabolic and mental risk factors is important for selecting preventive and/or therapeutic strategies in both men and women.

Lifestyle.
Undesirable lifestyle factors, such as smoking, alcohol abuse, and obesity, are crucial in comorbid hypertension and anxiety. First, chronic exposure to tobacco smoke alters the autonomic nervous system's regulation of BP, resulting in hypertension due to an unrestrained increase in sympathetic activation [26]. Furthermore, cigarette smoke contains chemicals that activate oxidative stress. Hypertension is caused by vascular infammation and aging due to increased superoxide generation [29]. Strikingly, there was a strong link between smoking >20 cigarettes per day and an elevated risk of anxiety [27]. Interestingly, smoking exacerbates anxiety in many ways, including nicotine withdrawal symptoms, perceived and real health impairments, and physical illness [28]. Second, alcohol elevates BP in a dose-dependent manner. Heavy alcohol consumption increases the risk of hypertension by altering the heart or vascular smooth muscle and stimulating the sympathetic nervous system or the renin-angiotensinaldosterone (RAS) system [30]. Alcohol abuse can exacerbate anxiety. Chronic alcohol abuse alters brain physiology, resulting in psychological sequelae. Furthermore, a paucity of coping responses and a sense of helplessness, inadequacy, and anxiety can be caused by alcohol intoxication during stressful situations [31]. Furthermore, alcohol abuse increases the engulfment capacity of microglia, causing aberrant synaptic pruning, synapse loss, and anxiety-like behaviors [32]. Tird,  [23][24][25] Smoking Increased sympathetic activity Nicotine-based withdrawal symptoms, perceived and objective health impairment [26][27][28][29] Oxidative stress Alcohol abuse Increased sympathetic activity Abnormal brain function [30][31][32] Activation of the renin-angiotensin-aldosterone system Obesity Abnormal kidney function; Senescent cells [33,34] Increase in tubular sodium reabsorption

Intensive oxidative stress
Excessive stress hormone release [37,38] International Journal of Hypertension 3 obesity is a signifcant predictor of various chronic disorders. Numerous epidemiological studies have demonstrated that being overweight or obese causes 65%-75% of primary hypertension cases. Obesity-related hypertension is initiated by impaired kidney function and increased tubular salt reabsorption [33]. Obesity is associated with various neurodegenerative disorders, particularly anxiety [34]. Te primary reason is obesogenic lifestyle factors such as dense caloric diets and inactivity. Mechanically, senescent glial cells exhibit excessive fat deposition, and obesity causes glial cell senescence, which generates anxiety [44]. Collectively, lifestyle risk factors are indispensable in the development of comorbid hypertension and anxiety.

Environment.
Environmental risk factors are associated with the exposure to Pb and trafc noise. Lead, one of the most common environmental stressors, can cause irreversible damage to the central nervous system, especially during development. Extended and desultory exposure to lead causes neuroinfammation, characterized by astroglial and microglial gliosis. Both anxiety and hypertension are caused by neuroinfammatory processes that develop over time [35]. In addition, hypertension can be caused by baroreceptor and chemoreceptor refex dysfunction due to intermittent or persistent lead exposure [36]. A recent study suggested that lead exposure generates oxidative stress and induces gut dysbiosis, which can lead to hypertension and anxiety [45]. Consequently, people exposed to lead are at high risk for comorbid hypertension and anxiety, especially those with occupational exposure. Trafc noise (from roads, aircraft, and railways) is a potential risk factor for cardiovascular and mental illnesses [46]. Trafc noise disrupts and shortens sleep, elevates stress hormone levels, and causes severe oxidative stress in blood vessels and the brain. Tese compounds facilitate infammation, endothelial dysfunction, and hypertension [37]. Increased exposure to trafc noise is considered a signifcant risk factor for anxiety. It is generally recognized that trafc noise is regarded as a formidable neurological stressor [38]. Overall, environmental risk factors negatively impact the cardiovascular and neurological systems during the early stages of development. It is imperative to implement public policy measures to mitigate the negative consequences of these environmental risk factors.
Age, sex, smoking, alcohol abuse, obesity, lead exposure, and trafc noise contribute to the development of comorbid hypertension and anxiety. Preventive measures such as risk factor screening and early management can enhance patient well-being. More importantly, the specifc mechanisms involved in comorbid hypertension and anxiety require further exploration.
IL-6 is related to angiotensin II (Ang-II)-mediated hypertension [48]. IL-6 is enhanced in response to exogenous Ang-II infusion, which increases the activity of the RAS system and ultimately causes hypertension to occur and develop [49]. Furthermore, IL-6 stimulates IL-17 production by inducing the polarization of CD 4+ T cells, resulting in hypertension [50,51]. IL-6 may trigger obesity by inducing hepatic gluconeogenesis and inhibiting lipid metabolism, thereby facilitating hypertension [52]. Similarly, individuals with anxiety disorders have elevated circulating IL-6 levels [53]. IL-6 levels are elevated in blood during repeated social defeat [54]. Increased IL-6 levels activate the bone marrow-derived peripheral monocytes and promote their recruitment to neurovascular endothelial cells, thereby releasing IL-1β and triggering anxiety [55,56]. Because of reduced amygdala volumes, maternal IL-6 levels can predict ofspring anxiety [57]. Terefore, IL-6 levels are closely associated with anxiety. Here, the functions of IL-6 in hypertension and anxiety were unclear. Despite the abundance of available studies, more experiments are required to understand the pathophysiological efects of IL-6.

IL-17.
IL-17 induces the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) on threonine 495 in a Rho kinase-dependent manner, resulting in decreased NO generation and the development of hypertension [58]. Additionally, IL-17 reduces lumen diameter and increases wall thickness, which induces inward hypertrophy and arterial stifness and results in hypertension [59].
IL-17 promotes anxiety development through neuronal IL-17A receptor (IL-17Ra) signaling in the medial prefrontal cortex [60]. Additionally, the astrocyte markers glial fbrillary acidic protein (GFAP) and brain-derived neurotrophic factor (BDNF) expression were also reduced by IL-17 [61]. Reductions in both GFAP and BDNF levels are vital mediators for the advancement of anxiety [62,63]. Consequently, we hypothesize that IL-17 is involved in the corporate etiology of comorbid anxiety and hypertension.

Reactive Oxygen Species (ROS).
Nicotinamide adenine dinucleotide phosphate oxidase (NOX) and mitochondria are the major enzymatic sources of ROS in the cardiovascular system [64]. Te production of ROS by NOX promotes to mitochondrial ROS production by causing mitochondrial DNA damage and oxidation of components of the membrane permeability transition pores [65]. Moreover, excessive ROS generation damages biological components, such as nucleic acids, proteins, and lipids, leading to cell damage and death. Several human diseases, including cancer, Alzheimer's disease, hypertension, and anxiety, are believed to be caused by these mechanisms [66]. Moreover, abundant ROS and infammatory factors, including IL-6 and tumor necrosis factor-α (TNF-α), contribute to comorbid hypertension and anxiety in rats [67]. Antihypertensive drugs (candesartan and azelnidipine) signifcantly reduce ROS and IL-6 levels [68,69].
Additionally, candesartan improves BP and hippocampal neurogenesis, and is an efcacious treatment for cardiovascular disease and mental illness [69].
Moreover, ROS is closely associated with hypertension as they promote the formation of isoketals. Hypertensive individuals exhibit signifcant isoketone expression [77].ROS induces the formation of isoketals, accumulating in dendritic cells (DCs). Accumulation of isoketals promote DC activation of T cells, which release IL-17 and IFN-c that cause aortic stifening, ultimately leading to overt hypertension [78]. Additionally, increased ROS levels are caused by many maternal conditions, such as obesity and smoking. Superfuous ROS then causes gut dysbiosis and RAS dysfunction in ofspring, contributing to the generational programming of hypertension in adult ofspring [79]. Terefore, ROS facilitates the incidence and development of hypertension ( Figure 1).
Glyoxalase (GLO)-1 and glutathione reductase (GSR)-1 are specifc antioxidant enzymes. ROS decreases the expression of (GLO)-1 and (GSR)-1 [82], and further enhances the level of anxiety by increasing infammation and synaptic plasticity [85]. Amazingly, ROS upregulates the expression of IL-6 and TNF-α and angiotensin (AT)-1 receptors by activating NF-κB generation. Tis process is involved in the development of hypertension and anxiety [67] (Figure 1). Given the detrimental roles of ROS in hypertension and anxiety, targeting ROS is a potential therapeutic strategy.

Gut Microbiota.
Te gut microbiotas play a vital role in promoting health. Gut microbiotas are microorganisms that colonize the digestive tract. Teir functions include the digestion of food, elimination of toxins, regulation of immunity, regulation of metabolism, and induction of International Journal of Hypertension neurogenesis [86][87][88]. Gut dysbiosis plays a decisive role in disease susceptibility. Microbial communities can be disrupted by nutrition, long-term antibiotic use, stress, and gastrointestinal disorders. Tis process is referred to as gut dysbiosis. Individuals with gut dysbiosis, are characterized by the loss of microbial diversity and benefcial microorganisms and an increase in potentially harmful microbes [89]. Recent studies confrmed the involvement of gut dysbiosis in the onset and progression of various diseases. Gut dysbiosis is particularly common in individuals with colorectal cancer [90], neurodegenerative disorders [91], kidney disease [92], obesity, type 2 diabetes, or arterial stifness [93].
Notably, the gut microbiotas of both prehypertensive and hypertensive populations showed decreased microbial richness and diversity than healthy populations [94]. Furthermore, considerable evidence supports the involvement of gut dysbiosis in exacerbating hypertension [95,96] because gut dysbiosis afects an individual's immune system and metabolism [97]. Additionally, gut dysbiosis contributes to anxiety by microbiota-gut-brain axis, which activates the vagus nerve and increases microbial metabolite production [87]. Changes in microbial metabolites, such as short-chain fatty acids (SCFs), trimethylamine N-oxide (TAMO), vitamin D, and 5-hydroxytryptamine (5-HT), play an indispensable role in the onset of hypertension and anxiety ( Figure 2).
Gut dysbiosis leads to a reduction of SCFAs, disrupting the intestinal barrier by decreasing ZO-1 and MUC-2. Te defciency of SCFAs promotes the production of PCs by stimulating the LPS-TLR4 pathway, inducing renal infammation leading to hypertension. Te defciency of SCFAs causes the overactivation of HPA axis by increasing the level of LPS, resulting in hypertension and anxiety. Te defciency of SCFAs exaggerates neuroinfammation by increasing IL-1β and IL-6 expression in the hippocampus, thereby promoting anxiety through inhibiting BDNF-GABA signal pathway. Te defciency of SCFAs reduces synapses via expediting microglial overactivation, inhibiting nerve conduction, and causing anxiety. Gut dysbiosis promotes the release of TMA into the bloodstream, further oxidized to TMAO. TMAO penetrates BBB, subsequently inhibiting MsrA expression promoting microglial overactivation, causing anxiety. TMAO promotes SDHB expression and inhibits SIRT1 expression, leading to ROS generation, which stimulates Ox-LDL secretion, reducing the production of
Similarly, the absence of SCFAs causes anxiety by reducing c-aminobutyric acid (GABA) and promoting microglial overactivation. Te absence of SCFAs potentiates neuroinfammatory responses by enhancing the expression of proinfammatory cytokines (IL-1β and IL-6) in the hippocampus. Signifcantly, exaggerated neuroinfammation arrests t BDNF expression [111]. Moreover, reduced

International Journal of Hypertension
GABAergic transmission is the way that BNDF deprivation promotes anxiety [112]. In addition, the absence of SCFAs expedites microglial overactivation, which reduces the number of synapses between neurons in the prefrontal cortex, thereby inhibiting nerve conduction and causing anxiety [32]. Te supplementation of SCFAs lowers BP [113] and anxiety levels [114]. Hence, SCFAs are potential therapeutic targets for comorbid hypertension and anxiety.
TMAO is also a critical contributor to anxiety. In the hippocampus, TMAO inhibits the antioxidant enzyme methionine sulfoxide reductase A (MsrA) by penetrating the blood-brain barrier. Te absence of MsrA in microglia promotes microglial overactivation by enhancing ROS production and NF-kB activity [123,124]. Moreover, the probiotic application reduces TAMO levels, further alleviating anxiety in anxious patients [125]. Tis evidence suggests that TMAO plays a crucial role in the progression of hypertension and anxiety.

Vitamin D.
Hypertension and anxiety are more common in individuals with vitamin D defciency [126]. Gut dysbiosis is closely associated with hypertension and anxiety by inhibiting vitamin D production. Gut dysbiosis decreases vitamin D levels, increasing the risk of hypertension [127]. Te mechanisms underlying vitamin D defciency-related hypertension include increased renin expression, hypocalcemia, and hyperparathyroidism [128]. Additionally, vitamin D disrupts the integrity of neurons by downregulating neurotrophic factors (neurotrophin-3 and neurotrophin-4) in the hippocampus and neocortex, causing anxiety [129]. Tus, vitamin D defciency may lead to hypertension and anxiety.

5-Hydroxytryptamine (5-HT).
Gut dysbiosis suppresses 5-HT secretion and contributes to hypertension and anxiety. Tryptophan is produced by Lactobacillus and Bifdobacterium. In enterochromafn cells, tryptophan hydroxylase 1 (TPH1) catalyzes the conversion of tryptophan to 5-hydroxytryptophan (5-HTP) in the colon. Tryptophan and 5-HTP can enter the brain and become precursors of 5-HT in the central nervous system [130]. Gut dysbiosis suppresses tryptophan secretion by decreasing the abundance of Lactobacillus and Bifdobacterium, suppressing the secretion of 5-HT [131]. Te abatement of 5-HT exacerbates insulin resistance and leads to obesity and hypertension [132]. Consistently, a reduction in 5-HT levels accelerates the occurrence of anxiety. Additionally, selective serotonin reuptake inhibitors can increase the concentration of 5-HT in synapses, reduce anxiety, and control the risk of hypertension [133]. In summary, gut microbiotas intensify hypertension and anxiety by suppressing 5-HT secretion.

4.4.5.
Others. Gut dysbiosis increases intestinal MYC expression and aggravates hypertension and anxiety. MYC is a highly pleiotropic transcription factor that broadly afects cell proliferation, metabolism, angiogenesis, apoptosis, and diferentiation [134]. Recent studies have suggested that gut dysbiosis increases MYC expression in the intestine. Subsequently, abundant intestinal MYC targets ceramide synthase 4 (Cers4) to stimulate ceramide synthesis and simultaneously decrease glucagon-like peptide 1 (GLP-1) secretion, facilitating obesity [135]. c-MYC, a member of the MYC family, induces anxiety by upregulating the expression of 5HT2AR and 5HT1AR [136].
Tese fndings suggest that gut dysbiosis is a risk factor for hypertension and anxiety. Targeting gut microbiotas may be a novel therapeutic option for patients with comorbid hypertension and anxiety.

Conclusion
Te increasing prevalence of comorbid hypertension and anxiety has a negative impact on treatment efcacy and quality of life. Understanding these population risk factors and physiological mechanisms will guide future clinical care for a population at increased risk for comorbid hypertension and anxiety. As discussed previously, the risk factors for comorbid hypertension and anxiety mainly include age, sex, smoking, alcohol abuse, obesity, lead exposure, and trafc noise. Aging is associated with an increased risk of comorbid 8 International Journal of Hypertension hypertension and anxiety. Hormonal changes make women more likely to develop comorbid hypertension and anxiety. Moreover, undesirable lifestyle factors such as smoking, alcohol abuse, and obesity, play a crucial role in comorbid hypertension and anxiety. Additionally, people exposed to lead and trafc noises are highly prone to comorbid hypertension and anxiety. Hence, optimizing lifestyle or living environment remains the cornerstone in preventing and treating of hypertension and anxiety. Furthermore, IL-6, IL-17, ROS, and gut dysbiosis are potential mechanisms underlying comorbid hypertension and anxiety. An increase in IL-6, IL-17, and ROS levels can promote the occurrence of comorbid hypertension and anxiety. Changes in SCFs, TAMO, vitamin D, and 5-HT caused by gut dysbiosis play essential roles in the occurrence and development of hypertension complicated by anxiety. Similarly, the changes in SCFs, TAMO, vitamin D, and 5-HT caused by gut dysbiosis play important roles in the occurrence and development of hypertension complicated by anxiety. Terefore, screening for hypertension complicated by anxiety and assessing its risk factors is necessary. Further studies should focus on the mechanisms involved in comorbid hypertension and anxiety and identify drug targets that can treat hypertension complicated by anxiety, to improve the efectiveness of treatment.

Prospection
Autophagy is an evolutionarily conserved self-digestion process, essential for cellular homeostasis [137]. Autophagy declines with age and may increase the risk of agerelated cardiovascular diseases [138]. Knockdown of autophagy-related genes (ATG) 5/7 suppresses Weibel-Palade bodies (WPB) in EC, thereby inhibiting endothelial diastolic function [139]. Similarly, mice suppressed essential gene (Ulk2) initiate autophagy and anxiety-like behavioral abnormalities [140]. Dysfunctional autophagy has been linked to gut dysbiosis and increased epithelial permeability [141]. Moreover, the defciency of the mitochondrial autophagy-related gene (ATG16L1) increases the number of mitochondria and produces numerous ROS [142]. Given its role in endothelial dysfunction and ROS activation, autophagy may be a potential target for comorbid hypertension and anxiety. Owing to the lack of direct evidence, more studies are needed to explore the exact efects of autophagy in comorbid hypertension and anxiety.

Clinical Implications
Te comorbidities of chronic mental and physical conditions complicate medical treatment and may expedite disease severity and progression. Anxiety and hypertension are common and often comorbid conditions treated during diagnosis and treatment process [143]. Terefore, healthcare systems and clinical care teams should focus on interventions to improve the screening, diagnosis, and timely treatment of hypertension comorbid anxiety. Efective, sustainable interventions are urgently needed to improve the screening and treatment of patients with comorbid hypertension and anxiety. Tis study summarizes the risk factors for hypertension and comorbid anxiety and provides a theoretical basis for medical staf to screen patients with comorbid hypertension and anxiety. Additionally, this study described some common underlying mechanisms of hypertension and anxiety, including IL-6, IL-7, ROS, and gut dysbiosis, which are expected to become therapeutic targets for patients with comorbid hypertension and anxiety.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
Tingting Qiu and Zhi-Ming Jiang contributed equally to this work.