Desenvolvimento de um escore genético de risco para avaliação de prognóstico em pacientes com insuficiência cardíaca de fração de ejeção reduzida

Abstract

The use of genetic risk scores is being successfully tested in some clinical settings. Nevertheless, for heart failure (HF), there is no description of a robust genetic panel for prognostic evaluation of these patients yet. The objective was to evaluate the relationship between a genetic risk score (GRS) and clinical outcomes in individuals with HF with reduced ejection fraction. In a cohort of 178 patients, the SNP variants of beta 1 adrenergic receptor (ADBR1), angiotensin converting enzyme, nitric oxide synthase, aldosterone synthase and angiotensinogen were identified. The GRS development process consisted of two consecutive stages. The GRS was built from five multisystemic single nucleotide polymorphisms (SNP). First, the relationship between ADBR1 genotypes and clinical outcomes was evaluated. These findings were contemplated in addition to other publications to select the risk alleles. GRS was calculated from the sum of the number of risk allele copies of each SNP (variation: 0-10). The population was divided into two strata according to disease time: Early-Stage HF (<72 months) or End-Stage HF (&#8805;72 months). The main clinical outcomes were: death and hospital admission due to HF. A significance level of 5% was adopted. The following results were observed: cohort means were: 63.5% of men and 55.1% of whites. HF etiologies were mainly ischemic (31.5%), idiopathic (23.6%) and hypertensive (15.7%). Preliminary analysis was done at 6.7 years of follow-up and 8.9 years of HF duration and mean age 64.4 years. There was a significant relationship between ADBR1 genotypes and clinical outcomes: Gly-Gly was related to better outcomes (p=0.026). Multivariate analysis defined the Gly allele as an independent predictor of reduction in death by 63% (p=0.03, OR 0.37 CI: 0.15-0.91). Subsequent findings evaluating the impact of GRS were analyzed at 8.1 years of follow-up, 10.3 years after HF diagnosis and mean age of 65.8 years. GRS was divided into two ranges according to the number of risk allele copies: Low (0-5) and High (6-10). High GRS was found in 123 patients (69.1%). High GRS was associated with lower survival in early-stage HF (p=0.018). In a multivariate analysis, High GRS was associated with double risk of death (HR=2.01; CI 1.21 3.33; p=0.007). There was no significant association between GRS and clinical outcomes or survival after 72 months of disease. In conclusion: ADBR1 Genotype was independently related to outcomes in HF: Gly-Gly patients presented with better outcomes and Gly allele was a predictor of lower mortality. The GRS, elaborated from five SNP, was identified as a predictor of survival in early-stage HF. The subgroup with High GRS was associated with double risk of mortality irrespective of other factors.