ABC | Volume 112, Nº4, April 2019

Original Article de Faria et al Inflammatory score and resistant hypertension Arq Bras Cardiol. 2019; 112(4):383-389 Table 3 – Independent multiple logistic regressions to evaluate the association of the inflammatory score with the presence of resistant hypertension OR (95%CI) p-value Model 1 IS 1.20 (1.02-1.38) 0.02 Model 2 IS 1.10 (0.92-1.28) 0.35 BMI (Kg/m 2 ) 1.12 (1.05-1.20) < 0.01 Model 3 IS 0.97 (0.80-1.18) 0.73 WC (cm) 1.04 (1.01-1.07) 0.01 Model 4 IS 1.00 (0.84-1.19) 0.96 FM (Kg) 1.08 (1.04-1.13) <0.01 All models were adjusted for age, gender and race. IS: inflammatory score; BMI: body mass index; WC: waist circumference; FM: fat mass. been suggested to be involved. 28-30 Interestingly, impaired microvascular function in obese subjects was normalized one year after a gastric bypass surgery, and it was also associated with BP reduction. 31 Elevated levels of free fatty acids lead to endothelial dysfunction by reducing the production of NO, and increasing endothelin-1 vasoconstrictor tone and the release of pro-inflammatory cytokines 32 – which is an early hypertension- related factor associated with future cardiovascular events. 33,34 Our findings showed that the association of IS and RHTN was abolished when the influence of body fat parameters was considered. Moreover, the IS was no longer significant after exclusion of obese subjects from both groups (data not shown). Our proposed score revealed its high dependence on obesity in the RHTN population, although this is expected since it is well‑known these subjects are predominantly obese/ overweight, as we found in our study – prevalence of 88%. Accordingly, the IS may reflect the inflammatory process underlying RHTN in an obesity-dependent manner, with the potential to be a clinical prognosis tool providing cardiovascular risk stratification in these obese subjects. On the other hand, we recognized that the design of this study is not sufficient to infer a temporal or cause-effect relationships. We also suggest that once obesity is established and hypertension is manifested, high BP may also contribute to further activation of inflammatory process. Thus, a vicious circle is created with both conditions – hypertension and obesity – that reinforces each other through inflammatory pathways. Pharmacological or non-pharmacological treatments may affect inflammatory cytokines/adipokines. Studies have indicated that simvastatin reduces plasma levels of TNF-alpha and IL-6. 35,36 Antihypertensive drugs such as candesartan, 37 enalapril, 38 and mineralocorticoid receptor antagonist have also been shown to reverse proinflammatory cytokines. 39 Indeed, exercise and lifestyle modification reduced IL-8 levels in subjects with the metabolic syndrome, 40 while significantly increased adiponectin levels in obese patients. 26 Nevertheless, although these potential sources of variability may be present, they probably did not affect our findings since RHTN subjects had a high IS even though they used a greater number of antihypertensive agents. The use of individualized care also justifies the lack of standard therapy, and due to ethical issues, our subjects could not be assessed withdrawing the drugs. Finally, in a perspective of therapy approach, anti-inflammatory drugs or anticytokine molecules targeting the immune system, such as minocycline, can be attractive and of great interest in clinical setting to treat hypertension and prevent its cardiovascular complications, as supported by previous works. 41-43 Some limitations should be mentioned. Since the population studied in this study is a convenience sample, with no sample size calculation, we recognize that our findings may not reflect the characteristics of the general population. Bias may also be present by comparing populations from different centers. It is worth mentioning that inflammatory process is quite complex and to measure its mediators is even more challenging since (i) it presents high costs, (ii) is still unavailable in clinical practice, and (iii) cutoff values may have heterogeneous profiles, which make the reproducibility more difficult. Even though, testing specificity and sensitivity in different populations are mandatory in order to guarantee a reliable score. Finally, this proposed score may change if the number of pro-inflammatory cytokines and/ or anti‑inflammatory cytokines changes. Conclusion In conclusion, our findings suggest that the IS, addressing many circulating cytokines/adipokines, may provide clinically important information to complement cardiovascular risk stratification in obese RHTN subjects. Moreover, our proposed score seems to be highly dependent on obesity-related hypertension. It is necessary to validate this score in larger populations in order to allow its use safely in clinical practice. Author contributions Conception and design of the research and writing of the manuscript: de Faria AP; acquisition of data: de Faria AP, Ritter AMV; analysis and interpretation of the data and critical 387