Implicações farmacogenéticas na resposta ao tratamento com Sacubitril/Valsartan ou terapias convencionais em pacientes com insuficiência cardíaca de fração de ejeção reduzida

Abstract

Heart failure (HF) is a chronic and multifactorial disease that affects millions of people worldwide, representing one of the main challenges to global public health. HF is classified into four main groups: HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), HF with preserved ejection fraction (HFpEF), and HF with improved ejection fraction (HFiEF). This study aimed to investigate the genetic basis of pharmacotherapeutic responses to Sacubitril/Valsartan in patients with heart failure with reduced ejection fraction (HFrEF). A total of 65 patients, aged between 40 and 89 years, were included in the study and followed at the Cardiology Service of HUPE-UERJ. Clinical and demographic data were obtained from medical records. Biological samples from 22 patients were collected for transcriptomic analyses using RNA-Seq to identify biomarkers associated with the efficacy of Sacubitril/Valsartan compared to conventional therapies, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). The analysis involved determining differential gene expression profiles, enabling the investigation of enriched biological pathways and contributing to the understanding of the molecular mechanisms related to treatment response. Other medication groups were also considered to rule out potential pharmacological interactions that could influence the results. The genomic ancestry of the 65 patients was determined using 46 ancestry-informative markers (AIMs) to assess the ancestral profile of the sample, correcting for potential biases that could affect data interpretation. The results demonstrated significant differences in the expression of genes involved in signaling processes and protein translation regulation, particularly in pathways such as neutrophil extracellular trap formation, selenocysteine synthesis, and response to amino acid deficiency. Additionally, ancestry analysis indicated homogeneity among the groups regarding the proportions of European, African, and Native American ancestry, eliminating potential biases due to population substructure. It was concluded that Sacubitril/Valsartan promotes specific molecular changes correlated with a superior clinical improvement profile in HFrEF patients treated with this drug compared to those treated with ACEIs or ARBs. Future validation of the identified biomarkers is suggested to advance personalized medicine in heart failure treatment.