Refractory hypertension (RfH) is an extreme phenotype of resistant hypertension (RH), being considered an uncontrolled blood pressure besides the use of 5 or more antihypertensive medications, including a long-acting thiazide diuretic and a mineralocorticoid antagonist. RH is common, with 10-20% of the general hypertensives, and its associated with renin angiotensin aldosterone system hyperactivity and excess fluid retention. RfH comprises 5-8% of the RH and seems to be influenced by increased sympathetic activity. RH patients are older and more obese than general hypertensives. It is strongly associated with diabetes, obstructive sleep apnea, and hyperaldosteronism status. RfH is more frequent in women, younger patients and Afro-americans compared to RFs. Both are associated with increased albuminuria, left ventricular hypertrophy, chronic kidney diseases, stroke, and cardiovascular diseases. The magnitude of the white-coat effect seems to be higher among RH patients. Intensification of diuretic therapy is indicated in RH, while in RfH, therapy failure imposes new treatment alternatives such as the use of sympatholytic therapies. In conclusion, both RH and RfH constitute challenges in clinical practice and should be addressed as distinct clinical entities by trained professionals who are capable to identify comorbidities and provide specific, diversified, and individualized treatment.

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Background:Refractory hypertension (RfHT) and obstructive sleep apnea (OSA) share common pathophysiological mechanisms and probably are intrinsically associated, but their prevalence, clinical profile, and polysomnography (PSG) pattern remain misunderstood.Objective:To describe OSA prevalence and PSG pattern of patients with RfHT in a large cohort of resistant hypertension (RHT).Methods:This is a cross-sectional study involving 418 RHT patients (30.9% male; mean age of 62.5 ± 9.9 years) who were submitted to full-night PSG. RfHT was defined as uncontrolled ambulatory blood pressure monitoring using five or more antihypertensive drugs, including spironolactone. Bivariate analysis compared RHT and RfHT and multivariate analysis was performed to assess the independent correlates of OSA.Results:A total of 90 patients (21.5%) were diagnosed with RfHT (26.7% male; mean age of 58.5 ± 8.3 years). In comparison with resistant ones, RfHT patients were younger, with higher smoking and previous cardiovascular diseases prevalence, especially stroke. There was no difference regarding anthropometric measures. OSA prevalence (80.0 vs. 82.9%) and moderate/severe OSA (51.1 vs. 57.0%) were similar in both groups as well as apnea–hypopnea index. In its turn, refractory hypertensive patients presented better sleep efficiency (78 vs. 71%), with higher total sleep time (315 vs. 281 min) and lower sleep latency (11 vs. 17 min). There was no difference regarding rapid eye movement sleep, oxygen saturation, microarousals index, and periodic limb movement.Conclusion:In this large RHT cohort, resistant and refractory hypertensive patients have similar OSA prevalence, although refractory ones, which by definition use spironolactone, are younger and apparently have a better sleep pattern.

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Objective: Introduction: Refractory hypertension (RfHT) is defined as an uncontrolled blood pressure (BP) despite the use of 5 or more antihypertensives, including spironolactone and it is considered an extreme phenotype of resistant hypertension (RHT). High BP levels lead to RAAS stimulation, sympathetic hyperactivity and endothelial dysfunction with consequent production of pro-inflammatory cytokines. Objective: To evaluate the relationship between inflammatory markers and refractory hypertension in a large cohort of patients with RHT. Design and method: A cross-sectional study that evaluated 423 resistant hypertensives (30.5% male, mean age 63.9 ± 10.8 years), of which 62 (14.6%) diagnosed as RfHT. All of them were submitted to the dosage of inflammatory markers: TNF-alpha, MCP-1, E-selectin and PAI-1. Socio-demographic and anthropometric characteristics and cardiovascular risk factors (CV) were recorded. Variance analysis compared serum levels of the 4 inflammatory markers and bivariate analysis compared patients with RHT versus RfHT. Results: Patients with RfHT are younger, with higher prevalence of smoking, higher levels of albuminuria and higher prevalence of chronic cerebrovascular and renal disease stages 4 and 5. PAI-1 values (126 [108–162] vs 118 [94–153] were higher in those with RfHT, although they did not reach statistical significance. The other biomarkers evaluated showed no association with the diagnosis of RfHT. Conclusions: Among inflammatory markers, PAI-1 was the one that correlated most strongly with refractory hypertension. Our study is the first one to demonstrate PAI-1 association with treatment refractoriness

Objective: Background: Resistant hypertension (RHT) defined as an uncontrolled blood pressure (BP) despite the use of 3 or more antihypertensives presents a high cardiovascular (CV) morbidity and mortality and high prevalence of chronic kidney disease (CKD). High BP levels and kidney injury appear to be strongly associated with inflammatory biomarkers. Objective: To evaluate the relationship between inflammatory markers and subclinical and established CKD in a large cohort of patients with RHT Design and method: Cross-sectional study that evaluated 423 resistant hypertensives (30.5% male, mean age 64.0 ± 10.8 years) submitted to renal function assessment (albuminuria dosage and evaluation of glomerular filtration rate calculated from the CKD-EPI formula) and dosage of inflammatory markers: TNF-alpha, MCP-1, E-selectin and PAI-1. Socio-demographic characteristics, anthropometric measurements and CV risk factors were recorded. We considered subclinical CKD those patients with moderately high albuminuria (30–300 mg/g) and/or GFR between 30 and 60 ml/min/1.73m2 and established CKD those who presented albuminuria > 300 mg/g and/or TFG < 30 ml/min/1.73m2. Variance analysis compared serum levels of the 4 inflammatory markers and bivariate analysis compared patients with and without subclinical and established chronic kidney disease. Results: The prevalence of established CKD was 7.3% (31 patients) and subclinical CKD was 47% (187 patients). Patients with subclinical CKD were older and with higher arterial stiffness (higher pulse wave velocity). TNF-alpha (7.1 [4.4–8.6] vs 51, [3.2–7.5]) and MCP-1(284 [220–379] vs 260 [185–359] were significant higher in this group of patients. When we analyzed patients with established CKD, we observed that they have higher BP levels and that TNF-alpha values (7.8 [5.6–14.0] vs 5.6 [3.5–8.3]) and E-selectin (54.4[41.2–61.3] vs. 47.8 [32.0–65.3]) were significantly higher in this group. Conclusions: Among the inflammatory markers evaluated, which was most strongly correlated with subclinical CKD were TNF-alpha and MCP-1, while those with established CKD have higher TNF-alpha and E-selectin levels, possibly pointing out that the MCP-1 is an earlier marker of kidney injury.

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