Hypertension in the context of cardiovascular disease
In Brazil, cardiovascular diseases (CVD) accounted for 30 % of deaths in 2008, with hypertension alone affecting more than 36 million people [
1]. In the United States, this figure is even higher, as approximately 80 million Americans have hypertension [
2].
As one of the main risk factors for the development of CVD, hypertension is the starting point of cardiovascular, cerebrovascular, and renal impairment. In most cases, by the time there is a manifestation, this disease, although still manageable, is irreversible. The main risk factors associated with hypertension are smoking, physical inactivity, stress, alcohol consumption, age, obesity, and an unhealthy diet [
3], all of which can alter the integrity of the vascular endothelium and lead to a number of complications.
Currently, a broad therapeutic arsenal is available for the treatment of hypertension. Nonetheless, sometimes hypertension becomes difficult to control due to varying situations, thereby characterizing resistant hypertension (RH), which requires a more intensive therapeutic approach. RH is a condition in which the blood pressure (BP) remains above the recommended target even when treated with the maximum tolerated doses of three antihypertensive drugs with synergistic actions, including a diuretic. A condition exists that is known as controlled resistant hypertension, which is defined as high BP that is controlled using four antihypertensive drugs [
4]. Although the exact prevalence of RH has not yet been precisely established, this state is estimated to occur in 12–15 % of the hypertensive population [
5]. The risk factors associated with RH are similar to those of hypertension; however, it is more common in elderly patients; females; Blacks; obese patients; physically inactive patients; and those with left ventricular hypertrophy, diabetes mellitus, chronic renal disease, metabolic syndrome, and high sodium intake [
4].
Hypertension and inflammatory markers
The long-term effect of RH on the vascular system can be catastrophic. Currently, vascular abnormalities are known to exist early in the development of hypertensive diseases and may manifest as severe endothelial dysfunction.
Endothelial dysfunction is considered an early marker of vascular complications. It participates in the pathophysiology of atherogenesis, which occurs in one of the first stages of arterial disease [
6,
7] as a result of risk factors that promote oxidative stress and nitric oxide (NO) inactivation [
8]. Endothelial dysfunction involves several functional changes: impaired endothelium-dependent vasodilation, changes in the endothelial barrier function, inflammatory activation, and stimulation of coagulation [
9]. Proinflammatory changes seem to be involved in the development of hypertension and in many other situations, including aging, diabetes, dyslipidemia, smoking, and obesity [
10‐
13]. These changes are characterized by a series of highly specific and essentially inflammatory, cellular, and molecular responses that lead to endothelial injury. Environmental factors such as salt intake and psychosocial stress may contribute to the activation of systems that participate in the pathogenesis and progression of hypertension. Moreover, both the sympathetic nervous and renin-angiotensin-aldosterone systems have very important roles, as there are correlations between the activation of these systems and increased inflammatory activity in hypertensive subjects. Thus, hypertension seems to be associated to inflammatory disorders [
13]. The inflammatory process is characterized by infiltration of macrophages and T lymphocytes in the endothelium. Activated lymphocytes and macrophages release a variety of inflammatory mediators such as cytokines, adhesion molecules, and matrix metalloproteinases (MMPs), resulting in increased inflammatory cell recruitment, the migration and proliferation of endothelial cells, platelet aggregation, and the release of free radicals [
11,
14].
Several inflammatory markers, such as proinflammatory cytokines, interleukins (IL-1β, IL-6, IL-8, IL-18), and tumor necrosis factor (TNF-α) related to activated monocytes, have been identified in these situations. Elevated expressions of intercellular adhesion molecule-1 (ICAM-1) in endothelial cells [
11,
15,
16] and highly sensitive C-reactive protein (hsCRP) have also been found. Recent studies show that cardiovascular risk is twice as high in patients with elevated hsCRP compared to patients with lower values. The hsCRP also has an effect on the endothelial surface as the migration and adhesion of monocytes increases, causing the synthesis of chemotactic factors due to the secretion of other proinflammatory factors, such as TNF-α, IL-6, and IL-8 [
13,
17]. In addition to proinflammatory cytokines, other cytokines with anti-inflammatory activity, such as IL-10, are present.
In animal studies, IL-10 has demonstrated protective roles against the stability and formation of atherosclerotic lesions. Some clinical studies have shown that patients with acute coronary syndrome have reduced IL-10 levels compared to stable patients, raising the possibility that low levels of IL-10 may be related to atherosclerotic plaque instability [
18].
Vascular endothelial dysfunction also promotes inflammation by inducing the production of vasoconstrictor agents, adhesion molecules, and growth factors, including angiotensin II (Ang II). Ang II, one of the end products of the renin-angiotensin system (RAS), is actively involved in the pathogenesis/pathophysiology of hypertension. It may be responsible for triggering endothelial dysfunction and vascular inflammation by inducing oxidative stress, a fact that results in the release of inflammatory mediators and in cell growth [
12,
13,
18,
19]. Some studies have demonstrated that Ang II increases the expressions of IL-6, IL-8, IL-18, and the monocyte chemoattractant protein (MCP-1), the last of which is the main regulator of leukocyte recruitment to the vascular wall. In addition, Ang II stimulates the expression of ICAM-1 and the infiltration of macrophages independently of the increase in BP [
19,
20].
The role of Ang II as a proinflammatory mediator of vascular injury is supported by the protective anti-inflammatory effects of RAS inhibitors. Among other effects, RAS inhibitors have properties that result in antithrombotic and fibrinolytic actions. The thrombogenic status mainly results from a high concentration of plasminogen activator inhibitor (PAI-1), which leads to an excessive accumulation of fibrin inside vessels, a situation that contributes to vascular events [
14]. Thus, PAI-1 is considered an important regulator of thrombogenesis; increased thrombogenesis can increase the risk of atherothrombotic events and promotes the progression of vascular disease [
21].
Fibrinogen, an acute phase protein, and cytokines are also directly related to vascular disease [
22]. Prospective studies on healthy subjects demonstrated a direct and independent association between the plasma fibrinogen levels and the risk of coronary and cardiovascular events and mortality [
16].
As previously mentioned, vascular inflammation and oxidative stress play a crucial role in the pathogenesis of vascular injury mediated by Ang II. Recently, angiotensin-converting enzyme 2 (ACE-2) was identified as having a pleiotropic effect on Ang II, resulting in the neutralization of its proinflammatory and pro-oxidant actions via receptors. Interestingly, the Ang II type-1 receptor blockers may increase ACE-2 expression and activity, thereby reducing cardiovascular and oxidative damage [
23].
MMPs are responsible for the degradation of extracellular matrix proteins, breaking them down into their specific peptide bonds, including the cells of the vascular smooth muscle, endothelium, fibroblasts, and inflammatory cells [
24‐
26]. The interaction of MMPs with their endogenous tissue inhibitors (MMP tissue inhibitors - TIMPs) is important among the factors that regulate MMP activity [
27‐
29]. Under physiological conditions, a balance exists in the ratio of MMPs and TIMPs. However, during pathological processes such as hypertension, an imbalance occurs that leads to excessive degradation of extracellular matrix proteins [
28] and, consequently, to pathological vascular remodeling. Among these proteolytic enzymes, MMP-9 has an important role in cardiovascular diseases, including atherosclerosis, coronary artery disease, vascular aneurysms, and hypertension [
30‐
36]. Studies suggest that increases in MMP-9 activity are associated with increased arterial stiffness not only in patients with isolated systolic hypertension but also in young individuals without comorbidities [
34,
36]. Notwithstanding these reports, studies are scarce that compare MMP levels with arterial stiffness markers in populations with different BP levels.
The aforementioned biochemical changes have a direct relationship with high BP, endothelial dysfunction, and increased vascular stiffness in RH patients, as is demonstrated by reduced flow-mediated vasodilation and increased pulse wave velocity (PWV), which result in higher central BP levels (CBP) [
37].
Central hemodynamics, sympathetic inhibition and hypertension
The CBP has a predictive value in the risk stratification of cardiovascular morbidity and mortality as demonstrated by the CAFE (Conduit Artery Function Evaluation) study. This study showed different effects on the CBP of groups treated with amlodipine and atenolol even though reductions in peripheral arterial pressure were similar. This difference has been suggested to be responsible for the favorable cardiovascular outcomes in the amlodipine group of the ASCOT study (Anglo-Scandinavian Cardiac Outcomes Trial), which demonstrated the importance of CBP control in relation to peripheral BP and how it can be influenced by certain drug therapies [
38].
The CBP is directly influenced by arterial stiffness; the arteries, especially the aorta and carotid, are estimated to stiffen by about 10 to 15 % in men and 5 to 10 % in women each decade [
39]. Arterial stiffness is a major determinant for the increase in the pulse pressure (PP) and CBP, variables considered risk predictors of myocardial infarction, stroke, and heart failure. In addition, higher cardiovascular morbidity and mortality have been associated with increased CBP, especially in hypertensive diabetics, the elderly, and chronic renal disease patients [
40,
41]. Thus, advanced age and high BP are the two most important variables for increased arterial thickness and, consequently, arterial stiffness.
The influence of arterial stiffness on the CBP explains why the pulse wave, generated in every left ventricular ejection period, propagates cyclically throughout the arterial tree to the peripheral arteries. Changes in the impedance and structural or geometric discontinuity of the arterial tree along its path generate reflected waves that move backwards into the ascending aorta and to the heart (backward wave). Therefore, the CBP is the sum of the anterograde and retrograde (reflected wave) components [
42,
43]. Wave propagation is amplified from the central aorta to the peripheral arteries. That is, the amplitude of the pressure wave will be greater in peripheral arteries than in the central arteries, which explains the increased pressure in the brachial artery compared to the aorta (central) in younger individuals (the CBP is about 10 to 20 mmHg lower than the peripheral BP). With aging, a loss occurs in arterial elasticity, increasing both the arterial stiffness and the PWV. Increased PWV causes a faster return of the reflected pulse wave with early overlap of the reflected wave during systole (unlike what happens in healthy young people when the reflected wave returns later in systole). This leads to an increase in the systolic pressure and elevation in central PP (PP amplification), which, in turn, increases the afterload on the left ventricle and reflects an increase in the CBP, which almost equals the peripheral BP [
43,
44]. This increase in the CBP caused by the reflection of waves is known as the augmentation index (AIx). Hence, the AIx is an alternative index derived from the analysis of the central aortic pressure curve and quantifies the effect of reflected waves [
45‐
47]. It has the advantage of taking into account the time of anterograde and retrograde waves, which are the main determinants of CBP.
Currently, nonpharmacological therapeutic methods are being used to treat RH. These are invasive, require long-term follow up to monitor the results and may cause unwanted complications during and after the procedure, besides being expensive. Examples of these methods are denervation or ablation of the renal sympathetic ganglia and chronic carotid baroreflex stimulation [
48]. Both these techniques have generated good results in the reduction of peripheral BP by improving vasomotor tone related to sympathetic suppression; however, similar reductions in BP were reported for treatment and placebo groups [
48,
49]. Thus, the identification of new noninvasive therapeutic approaches to control RH is essential. Transcutaneous electrical nerve stimulation (TENS) may be a new, easy to apply, reproducible, and inexpensive technique for this purpose. TENS is capable of inhibiting primary afferent pathways using low-frequency electrical pulses generated by electrodes attached to the skin, which cause local numbness and thus inhibit pain [
50,
51]. In addition to the analgesic effects, electrical stimulation has been shown to enhance a local vasodilator effect, which may contribute to reducing BP and prevent ischemia [
52]. Among the mechanisms that might explain this anti-ischemic action are the inhibition of sympathetic segmental vasoconstriction, release of vasodilatory peptides from sensory neurons, and the pump effect of muscle contractions [
53‐
56]. Other favorable effects have been observed on applying TENS in the cervicothoracic ganglion region. The cervicothoracic ganglion or stellate ganglion, whose predominant action is sympathetic activity, is a confluence of nerves located in the posterior cervical region at the junction of the lower and upper thoracic cervical ganglia [
53‐
58].
Mannheimer et al. demonstrated that low-frequency electrical stimulation applied to the suprathoracic lymph node region produced an anti-ischemic effect by reducing myocardial oxygen demand due to the reduction in the afterload resulting from a reduction in BP [
53]. This response, which is hypothetically based on the observed reduction in epinephrine and norepinephrine levels, may involve a reduction in sympathetic nervous system activation [
53,
57]. In turn, Silva et al. observed that TENS applied to the suprathoracic ganglion region during exercise might be associated with decreased peripheral and central BP in healthy young people, a response indicated by significant changes in heart rate variability [
58].
Given the scarcity of publications in the scientific literature, this innovative work will study the effects of the application of TENS in the suprathoracic lymph node region to reduce peripheral BP and CBP in RH patients.