Introduction: Cardiogenic shock (CS) is a life-threatening syndrome of cardiac pump failure. In this setting, inadequate renin-angiotensin-aldosterone system (RAAS) activity may contribute to impaired organ perfusion. Angiotensin-converting enzyme 2 (ACE2) counter-regulates RAAS by degrading angiotensin II into vasodilatory peptides and thus, may exacerbate hypoperfusion in CS. To date, soluble ACE2 (sACE2) activity has not been characterized in this population. This study compared sACE2 activity between patients with CS and stable heart failure (sHF) and investigates its association with mortality. Methods: Plasma samples were obtained from 339 CS patients within 24 hours of admission to the Toronto General Hospital between January 2014 and December 2020 and from 343 sHF patients, matched for age, sex, ejection fraction, and HF etiology. sACE2 enzymatic activity was measured using a fluorometric assay. Fine–Gray subdistribution hazard models were used to assess the association between sACE2 and mortality, accounting for the competing risks of left ventricular assist device placement and orthotopic heart transplantation. Models were adjusted for age, sex, CS severity, etiology, mechanical ventilation, creatinine, and sodium. Spearman correlation tested associations between sACE2 activity and 48 cytokines. Results: For the 682 patients included, the mean age was 56 (SD 15) with 27% being female. sACE2 activity was significantly higher in CS vs. sHF patients (median IQR 42.5 21.9 to 76.7 ng/mL vs. 25.3 16.0 to 38.0 ng/mL, p28.5 ng/mL) was independently associated with mortality at six months (HR 1.92, 95% CI 1.15-3.83, p=0.020), one year (HR 1.80, 95% CI 1.13-2.86, p=0.013) and three years (HR 1.90, 95% CI 1.12-3.23, p=0.018) post-admission. Elevated sACE2 activity was not associated with mortality in sHF. sACE2 activity positively correlated with the concentration of pro-inflammatory cytokines IL6 (ρ=0.169, p=0.002), IL8 (ρ=0.229, p< 0.001), and CXCL10 (ρ=0.140, p=0.012). Conclusions: Soluble ACE2 activity is elevated in CS compared to sHF and is associated with long-term mortality in this population. Further studies are needed to assess the prognostic value of sACE2 and its role in identifying patients who may benefit from RAAS-modulating therapies.
Baskaran et al. (Sun,) studied this question.