ABC | Volume 114, Nº3, March 2020

Statement Brazilian Position Statement on Resistant Hypertension – 2020 Arq Bras Cardiol. 2020; 114(3):576-596 characteristics are intuitive, others, including the female sex, still lack well-defined rationales in predicting RHTN. 6.3. Phenotype of Controlled and Uncontrolled Resistant Hypertension 6.3.1. Pathophysiological Aspects C-RHTN shows greater dependence on volume status than UC-RHTN, due to critical persistence of water retention, increased sodium sensitivity, hyperaldosteronism, and renal dysfunction. Additionally, these individuals present increased plasma volume expansionmeasured by thoracic bioimpedance, 77 higher plasma and urinary aldosterone concentrations, suppression of renin activity, 78 high plasma aldosterone/renin ratio (ARR), and increased levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). 79-83 This relationship between increased volume and pressure is the pathophysiological basis demonstrated in several studies 81,84,85 and justifies the use of diuretics in patients with C-RHTN. 86,87 In contrast, patients with UC-RHTN often have sympathetic hyperactivity, evidenced by increased (24-hour) urinary metanephrines and resting heart rate, reduced 24-hour variability (spectral analysis), in addition to increased vascular stiffness (increased PWV). 88,89 These markers of increased sympathetic activity, together with other factors linked to hyperaldosteronism, 78,90-92 are related to mechanisms that maintain high BP even with administration of four or more antihypertensive agents, characterizing UC-RHTN. Higher PWV values reflect exacerbated arterial stiffness, 4 while elevated levels of cytokines, including tumor necrosis factor- alpha (TNF- α ), 48,56,93 probably indicate vascular damage in patients with RHTN. 49 Other factors and mechanisms, such as age, obesity, OSA, 4,94,95 African descent, adipokine deregulation, 96 endothelial dysfunction, and increased activity of metalloproteinases-2, metalloproteinases-9 and adhesion molecules 97-99 are also involved in this process. Genetic polymorphisms, especially those involving the renin-angiotensin-aldosterone system and the endothelial nitric oxide synthase (eNOS), have been correlated to RHTN 100,101 (Figure 3). However, large studies conveniently characterized in individuals with the disease are needed to define the importance of genetics in this group of patients. 6.3.2. Clinical Differences In 2011, Martins et al. published a comparative study in patients with C-RH and UC-RHTN 4 specifically assessing biological factors contributing to resistance to antihypertensive agents. Body mass index (BMI), arterial stiffness (PWV), left ventricular mass index (LVMI), and plasma aldosterone concentration (PAC) were higher in the UC-RHTN group when compared with the C-RHTN group. Additionally, the authors demonstrated using multivariate analysis that PWV was dependent on age in both groups, although this influence was more pronounced in patients with UC-RHTN. They also showed that the UC-RHTN group had higher values of carotid intima-media thickness (cIMT) and PWV. 102 Finally, the drop in nocturnal BP (dipping pattern) was less pronounced in the UC-RHTN group. 103 6.3.3. Prognosis Pierdomenico et al. 104 evaluated CV outcomes in subjects with C-RHTN and UC-RHTN. The occurrence of fatal and nonfatal CV events was investigated in 340 patients with C-RHtN (BP < 140/90 mmHg or daytime BP < 135/85 mmHg) and 130 patients with UC-RHTN (BP ≥ 140 or 90 mmHg and daytime BP > 135 or 85 mmHg). During follow-up (4.98 ± 2.9 years), the event rates per 100 patients/ year were 0.87 and 4.1, respectively. These data also show that patients with UC-RHTN have a greater risk of CAD, stroke, Figure 3 – Predominant pathophysiological mechanisms in controlled (C-RH) and uncontrolled (U-RH) resistant hypertension. Refractory hypertension (uncontrolled with five or more medications) is included in the U-RH group. Resistant hypertension Controlled resistant hypertension (C-RHTN) Uncontrolled resistant hypertension (UC-RHTN) Persistent fluid retention Sympathetic hyperactivity Sodium intake Sodium sensitivity Aldosterone Sodium and water retention Chronic renal disease 24-h urinary metanephrines Heart rate (rest) Heart rate variability Arterial stiffness Peripheral vascular resistance 585