Reduced ACE-2 and Angiotensin 1-7 Activity in Acute Heart Failure
In acute heart failure, reduced ACE-2 or angiotensin 1-7 activity leads to an imbalance in the renin-angiotensin system that promotes inflammation, fibrosis, and vasoconstriction, contributing to worsening cardiac function and poorer clinical outcomes. 1
Pathophysiological Mechanisms
The reduction in ACE-2/angiotensin 1-7 activity during acute heart failure occurs through several mechanisms:
Viral-like downregulation: Similar to SARS-CoV-2 binding to ACE-2, acute stress can lead to internalization and downregulation of membrane-bound ACE-2, reducing its availability to convert angiotensin II to angiotensin 1-7 1
Dysregulated counter-regulatory balance: In acute illness including heart failure, the ACE/angiotensin II pathway becomes upregulated to maintain organ perfusion, but without a compensatory increase in the ACE-2/angiotensin 1-7 pathway, leading to an imbalanced system 1
Endothelial dysfunction: Acute heart failure is associated with endothelial dysfunction characterized by inflammation and oxidative stress, which can further reduce ACE-2 expression and activity 1
Increased ADAM17 activity: Stress and inflammation promote phosphorylation of ADAM17, causing subsequent ACE-2 cleavage from cell surfaces, reducing membrane-bound ACE-2 activity 1
Clinical Consequences of Reduced ACE-2/Angiotensin 1-7
The reduction in ACE-2 and angiotensin 1-7 activity leads to several detrimental effects:
Unopposed angiotensin II effects: Without adequate ACE-2 activity, angiotensin II levels rise without the counterbalancing effects of angiotensin 1-7, leading to increased vasoconstriction, sodium retention, and aldosterone production 1, 2
Pro-inflammatory state: Reduced angiotensin 1-7 levels fail to counteract the pro-inflammatory effects of angiotensin II, exacerbating myocardial inflammation 1, 3
Pro-thrombotic environment: ACE-2 normally has antithrombotic properties; its reduction promotes a pro-coagulant state through increased PAI-1 expression 1
Worsened clinical outcomes: A suppressed angiotensin 1-7/angiotensin II ratio is associated with worsening heart failure symptoms and longer hospitalization 2, 4
Evidence of ACE-2/Angiotensin 1-7 Reduction in Acute Heart Failure
Studies have demonstrated that in the acute phase of heart failure, angiotensin 1-7 concentrations are significantly lower while ACE-2 concentrations are paradoxically higher (likely as a compensatory mechanism) compared to healthy individuals 5
After optimal therapy for acute heart failure, ACE-2 levels normalize within 1 month, while angiotensin 1-7 levels take up to 3 months to return to normal levels 5
An elevated angiotensin 1-7/angiotensin II ratio predicts favorable outcomes in heart failure patients, including improved survival and decreased hospitalization duration 4
Clinical Implications
Therapeutic potential: Enhancing the ACE-2/angiotensin 1-7 axis represents a promising therapeutic target in heart failure management 3
Monitoring biomarkers: The angiotensin 1-7/angiotensin II ratio may serve as a prognostic indicator in heart failure patients 4
Medication considerations: ACE inhibitors enhance the release of tissue plasminogen activator and reduce PAI-1, potentially mitigating some effects of reduced ACE-2 activity 1
First-dose effects: When initiating ACE inhibitors in acute heart failure, be aware of potential first-dose hypotension due to the already dysregulated renin-angiotensin system 6
Understanding the role of reduced ACE-2 and angiotensin 1-7 activity in acute heart failure provides insights into disease pathophysiology and potential therapeutic targets to improve outcomes in these patients.