Resistant Hypertension An Open, Complicated ("Cum Plicare") or Complex ("Cum Plexus") Syndrome?

Resistant arterial hypertension (RAH) is a complex and multifactorial syndrome, with hyperactivity of the sympathetic nervous system (SNS) and reduction of vagal activity being considered some of the main causes of refractoriness to treatment. Seen from the outside, it resembles a complicated (see lat. "Cum plicate") or complex disease (see lat. "Cum plexus"), Chaotic with the participation of several open systems. For example, in recent years some relationships have been demonstrated between the autonomic nervous systems, synaptic mediators, hormones, inflammatory and immune responses. However, these findings have not been investigated together and systematically. In the present project, we intend to establish and compare, in an integrated way, the clinical alterations present in RAH (resistant and refractory), hemodynamic variables, autonomous activity (sympathetic and baroreflex) and interactions with the neuroimmune-endocrine systems. To this end, we will test the hypothesis that resistant patients have greater damage to the autonomic nervous system (ANS) associated with exacerbated systemic and hormonal inflammatory profile, including SNA mediators (noradrenaline and acetylcholinesterase). This is also intended to determine the behavior (deterministic or chaotic) of the systems evaluated (mentioned above) in volunteers with RAH. Sample and methods: The sample space (calculated) will consist of 72 individuals, being: - 18 refractory hypertensive (HRT); II- 18 resistant hypertensive patients (HRfT); III- 18 controlled hypertensive (1-2 drugs) (CAH); and IV- 18 healthy normotensive individuals. This is a prospective, double-blind study (patient and professional-technician), paired (1 X 4), in which the 72 volunteers will be evaluated by the methods set out below. We will also have the chance to observe whether resistant and refractory hypertension share the same pathophysiological bases and clinical manifestations ("deterministic-isolated or cardiovascular chaos") by analyzing the patterns of cardiovascular variability (MAPA and Holter) (SpaceLabs, USA; DynaMap, Brazil), inflammatory and hormonal mediators (ELISA) in the resistant hypertension - RHT and refratary hypertension - HfRT groups. Central pressure (CP) and arterial stiffness (pulse wave velocity, VOP) (Sphymocor, ATCor, USA) will also be assessed. Healthy normotensive (NT) and controlled hypertension (CAH) will be evaluated in an identical way to control the other groups. Perspectives: The findings will improve the clinical knowledge based on pathophysiology about Resistant Hypertension and, mainly, the bases of pharmacological treatment and with implantable devices (stimulation of baroreceptors and sympathetic denervation) used in this condition.

Cardiovascular Autonomic Modulation Procedures for spectral analysis of pulse interval (heart rate variability) and systolic blood pressure variability have been described in the literature41-44. Each heartbeat will be identified using a specialized algorithm implemented in Matlab MT software (MATLAB 6.0, Mathworks, USA ) and which automatically detects PAS and PAD waves. The pulse interval or R-R interval will be calculated as the difference between the start and end points of the cycle (t1-t0). The power spectral density of the PAS and R-R interval will be calculated using the Fast Fourier Transform and the Welch method over 16,384 points with a Hanning window and 50% overlap. The spectral bands evaluated for humans were defined according to literature references: very low frequency (MBF: 0.007-0.04Hz), low frequency (BF: 0.04-0.15Hz), high frequency (AF: 0. 15-0.4 Hz) and full power \[130\]. Baroreflex sensitivity will be inferred from the alpha index (HR BF ratio in ms2 / SBP BF ratio in mmHg).

ABPM - It will be performed with the CardioMAPA Monitor - Cardios - Brazil, with standardized measurements every 15 minutes during the waking period, and every 20 minutes during the sleeping period. The data will be considered valid when monitoring takes place for a minimum period of 21 hours with a minimum number of forty measurements during wakefulness and ten measurements during sleep.

Determination of Central Blood Pressure and Amplification Index (AIx) - The SphygmoCor CPV system (AtCor Medical, USA) is a sophisticated non-invasive diagnostic tool for clinical assessment of central blood pressure. This system derives central aortic pulse wave pressure (systolic, diastolic, and pulse) using pulse wave pressure recorded by the radial artery. Pulse wave analysis predicts parameters including PAC and indications of vascular stiffness. Measurements are made using a pressure transducer (tonometer) positioned in the required artery and then the pulse wave is recorded. Furthermore, this equipment provides information on arterial stiffness by analyzing the Augmentation Index \[Amplification Index (AIx)\], defined by the ratio between the pressure determined by the reflected wave and the ejection wave capable of providing information on arterial stiffness.

Assessment of Clinical Parameters - BP measurements will be taken according to the recommendations recommended by the VIII Brazilian Guidelines on Arterial Hypertension using a digital sphygmomanometer (Omron HEM-711DLX). Pulse pressure (PP) will be calculated from the difference between SBP and DBP values. All individuals will undergo ambulatory BP monitoring (ABPM) for a period of 24 hours using the Spacelabs 90217 equipment (Spacelabs Inc, Redmon, WA, USA). Patients will be instructed to maintain and record normal daily activities. The averages of SBP, DBP and PP will be evaluated.

Assessment of Biochemical and Inflammatory Parameters - Fasting blood samples will be collected and the following tests will be carried out: glucose, glycated hemoglobin A1C, total cholesterol and fractions, urea, creatinine, renin, aldosterone, cortisol, creatinine clearance and microalbuminuria. The biomarkers norepinephrine, dopamine, adrenaline, adrenocorticotropic hormones (ACTH) and cortisol, acetylcholinesterase, ultrasensitive C-reactive protein, interleukins 2, 8, 10 and 12 (IL-2, IL-8, IL-10 and IL-12) will be determined by ELISA according to the manufacturer's instructions.

Eligibility Criteria:
Inclusion Criteria:

* men and women over 35 years of age diagnosed with resistant arterial hypertension (RH), in accordance with the latest international and national guidelines;
* be able to understand, verbalize and answer questions;
* agree to participate in the study and sign the Informed Consent Form;
* after clearly understanding it;
* be under regular follow-up at the UNICAMP Cardiovascular Pharmacology outpatient clinic for at least six months;
* have proven adherence to non-pharmacological and pharmacological treatment;
* women in the reproductive phase must be using a proven effective contraceptive method.

Exclusion Criteria:

* clinical history or clinical symptoms of heart failure;
* patients with dilated cardiomyopathies, valvular heart disease, pericardial disorders;
* patients with cerebrovascular disease or peripheral arterial disease, nephropathies, liver diseases, smoking, autoimmune diseases and use of illicit substances;
* any abnormal condition that may interfere with the results of the study or the health of the volunteer, as judged by the researcher;
* women who are pregnant or intend to become pregnant;
* current participation in another investigative study;
* major depression or other relevant psychiatric disorders.