Pathophysiological Sex Differences in Heart Failure Progression AfterAcute Coronary Syndrome: Insights From the EXAMINE Trial

Autores da FMUP

• João Pedro Melo Marques Pinho Ferreira

  Autor

Participantes de fora da FMUP

• Razaghizad, A
• Aziz, H
• Zhang, GK
• White, WB
• Mehta, CR
• Bakris, GL
• Zannad, F
• Sharma, A

Unidades de investigação

• Cirurgia e Fisiologia

• Laboratório Associado RISE- Rede de Investigação em Saúde

  

  Investigador

  Fernando Carlos De Landér Schmitt

Abstract

Background: Therapies can reduce the risk of heart failure (HF) development and progression in type 2 diabetes; nevertheless, the risk of these outcomes is greater in females than in males. Methods and Results: To investigate sex differences in HF development and progression, we compared baseline circulating proteins (Olink Cardiovascular II panel) in males and females with type 2 diabetes and recent acute coronary syndrome for the outcome of HF hospitalization. Data were from the placebo-controlled Examination of Cardiovascular Outcomes with Alogliptin vs Standard of Care (EXAMINE) trial. Pathophysiological sex-differences were interpreted with network and pathway over-representation analyses. The EXAMINE trial enrolled 5380 participants (32.1% females) with biomarker data available for 95.4% of individuals. Analyses revealed 43 biomarkers were differentially expressed in HF hospitalization, of which 18 were sex specific. Among these 43 biomarkers, interleukin-6 was identified as a central node for the pathogenesis of HF hospitalization in both females and in males. Additional pathway over-representation analyses demonstrated that biomarkers associated with inflammatory pathways related to endothelial dysfunction and cardiac fibrosis were more up-regulated in females than males with HF hospitalization. Differential expression of 3 biomarkers (pentraxin-related protein 3, hydroxyacid oxidase 1, and carbonic anhydrase 5A) was independently associated with an increased risk of HF hospitalization in females but not in males (interaction P < .05). Conclusions: In males and females with type 2 diabetes and acute coronary syndrome, interleukin-6 seems to be central in the pathogenesis of HF. Females exhibit higher levels of circulating proteins related to immunological pathways, reflecting sex-specific differences underlying HF development and progression.

Keywords

• Proteomics; heart failure; diabetes; epidemiology; sex differences