ABC | Volume 114, Nº4, April 2020

Original Article Albuquerque et al. Ser49Gly Polymorphism in heart failure Arq Bras Cardiol. 2020; 114(4):613-615 Another even more relevant aspect is the clinical interpretation of this GP. In this case, it was possible to demonstrate that Gly‑Gly had a significant association with a surrogate clinical marker: final NYHA (p = 0.014). Individuals with this genotype had a better clinical outcome: no patient in this group showed advanced functional class at the end of the follow-up. Although it is a relatively small number of patients (five individuals), the longer follow-up time compared with other studies allowed the distinction of clinical behaviors among the genotypes. Considering that there were no baseline clinical differences among the three GPs, including treatment, the difference in the final NYHA found in this study suggests that genetic variations could influence the pathophysiology of heart disease. Therefore, genotyping could identify a subgroup of patients with HF with worse clinical outcome. This finding is an original one in the literature, as there are no publications on patients with HF correlating GPR β 1‑Ser49Gly to clinical outcomes, such as NYHA functional class. Because of that, it is not possible to compare this result with other populations, which would be appropriate to validate this finding. Despite its recognized prognostic value, NYHA functional class is an inaccurate marker of HF severity. The lack of inter‑examiner reproducibility has been described andmay limit its accuracy. 21 It also translates only one clinical aspect of the syndrome. In the future, it may be more appropriate to study the association of the genotype with more complete clinical scores, such as MAGGIC, 22 in which there is a combination of clinical, laboratory and echocardiographic variables. The high mortality rate found in this study – 37.6% – is probably due to the long follow-up time. For comparison purposes, Biolo et al. 10 found a mortality rate of 27.9% in Rio Grande do Sul and Pereira et al. 16 found 12.3% in Rio de Janeiro. Despite the disparity between these rates, there are similarities in the baseline characteristics of these populations: LVEF of approximately 30–35%, the majority (65–75%) of patients in NYHA I or II and an optimized therapy adopted. The most significant difference between the three studies is their follow‑up time: 80.4 months in this study, and 39.8 months 10 and 23 months 16 in the abovementioned studies, respectively. Assessment of the association of GP-R β 1 with mortality showed that the wild Ser-Ser allele concentrated most of these events and the Gly allele was consistently associated with a protective effect. The presence of each copy of the Gly allele was associated with a 63% reduction in the risk of death. This protective effect was maintained even after strict adjustment for the main variables used to stratify HF prognosis. Accordingly, in a hybrid model that incorporated genetic, clinical, laboratory, echocardiographic, treatment and physical examination variables, Gly-Gly remained with a high predictive value for the lower occurrence of deaths. In the literature review, the results are diverse, but mostly consistent with the current one. Those include studies that have found no association between GPR β 1-Ser49Gly and clinical outcomes, 10,16,23 studies with the same protective pattern as the Gly allele 7,17,24 and even a paper paradoxically associating Gly with poor prognosis in HF. 13 In line with our findings, the first studies of Borjesson et al. 7 (the first description of this GPR β 1-Ser49Gly), Forleo et al. 24 and Magnusson et al. 17 describe the protective profile of the Gly allele: significantly fewer deaths were observed with the genotypes Ser-Gly or Gly-Gly, even after adjusting for other variables. However, there is a study describing the opposite, i.e., the Gly allele associated with poor prognosis. Wang et al. 13 described GPR1-Ser49Gly in a Chinese population of 430 patients with HF and baseline characteristics similar to those of this study. The authors associated the Gly allele to worse echocardiographic outcomes and higher mortality. The contrast between these findings may be related to a different genetic impact on the ethnicities. Two pieces of evidence underlie this theory. Firstly, Pereira et al. 16 identified Ser-Ser as a factor of poor prognosis in a multi-ethnic population from the city of Niterói, state of Rio de Janeiro. Nevertheless, this pattern was only found in patients with black skin. This finding was also reproduced in the meta-analysis of Liu et al. 9 The analysis of 2,979 patients genotyped for Ar389Gly and Ser49Gly GP-R β 1 identified a specific pattern of the Gly389 allele for each ethnicity: association with higher risk of HF in Asian patients, while in whites, it was associated with a reduction of this risk. Along the same lines, the A-HEFT study described better response to nitrate and hydralazine combination for African- American patients. 25 Subsequently, McNamara et al. associated this benefit to a particular GP of Nitric Oxide Synthase, more frequent in African Americans compared to whites. 26 Likewise, the meta-analysis of Liu et al. 9 and the study by McNamara et al. 26 describe the variety of clinical effects among different ethnicities in the context of HF. This reinforces the need for specific studies targeted at Brazilian patients, as the behavior of these GPs for a population that is recognized as miscegenated is unpredictable. These examples reaffirm the genetic influence on the natural history of HF. Generally speaking, we acknowledge the pathophysiological response of the syndrome as a result of the activation of hormonal systems. However, at the molecular level, beta-adrenergic receptors and enzymes, such as nitric oxide synthase, are some of the important factors implicated in cardiac remodeling. The functional modification of these and other agents due to genetic polymorphisms may explain these multiple clinical outcomes in phenotypically similar patients. The process of neurohumoral response involves amultitude of elements, each potentially sensitive to diverse genetic mutations. In view of that, a genetic panel including the main systems (sympathetic nervous system, renin-angiotensin-aldosterone system and atrial natriuretic peptide) is likely to be more appropriate than a specific isolated polymorphism. The first step is to identify themain geneticmarkers for each system. In relation to the sympathetic nervous systemand the beta-adrenergic receptor, this study stresses the prominent role of the Ser49Gly GP. In the future, the construction of a multisystemic genetic score may prove to be a powerful prognostic predictor. Possibly, a score capable of identifying high-risk individuals, even at the onset of disease, when clinical findings and complementary tests are not yet significantly abnormal. 621