Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway.
Key result
Intracoronary enalaprilat reduced the fractional conversion of Angiotensin I to Angiotensin II by 89% in the intact human heart, demonstrating that the predominant pathway for Angiotensin II formation is through ACE.
Why the study?
Does enalaprilat reduce angiotensin II formation in the intact human heart?
Population
Orthotopic heart transplant recipients (n=5) and explanted human hearts (n=8 failing, n=7 nonfailing)
Comparison
Intracoronary enalaprilat or 1 microM enalaprilat vs Without enalaprilat
Design
Other
Authors
Discussion
Loading...
Member takes
Implication
ACE predominates cardiac Ang II formation; leaves open whether this extends to native failing hearts or alters ACEI dosing.
Key Points
- To determine the relative contribution of angiotensin-converting enzyme (ACE) versus non-ACE pathways to angiotensin II formation in the intact and explanted human heart.
- Administered intracoronary 123I-labeled angiotensin I with and without the ACE inhibitor enalaprilat to orthotopic heart transplant recipients to measure in vivo fractional conversion via HPLC.
- Quantified ACE activity and enalaprilat inhibition in vitro using solubilized left ventricular membrane preparations from explanted failing (n = 8) and nonfailing (n = 7) human hearts.
- Intracoronary enalaprilat reduced in vivo fractional conversion of angiotensin I to angiotensin II by 89%, decreasing from 0.415 ± 0.104 (n = 5) to 0.044 ± 0.053 (n = 4, P = 0.002).
- In vitro, 1 µM enalaprilat reduced membrane ACE activity by 85% in failing hearts (from 49.6 ± 5.3 to 7.3 ± 1.4 fmol/min/mg) and nonfailing hearts (from 35.9 ± 4.8 to 4.6 ± 1.3 fmol/min/mg, P < 0.001).
Structured PICO
Does enalaprilat reduce angiotensin II formation in the intact human heart?
P
Population
5 orthotopic heart transplant recipients and 15 explanted human hearts evaluated to determine the in vivo and in vitro contribution of ACE to angiotensin II formation.
I
Intervention
Intracoronary enalaprilat (in vivo) or 1 microM enalaprilat (in vitro)
C
Comparator
Without enalaprilat
O
Outcome
Fractional conversion of Ang I to Ang II (in vivo) and ACE activity (in vitro)surrogate
Main Result
Effect estimate: 89% reduction
Absolute Event Rate: 0.044% vs 0.415%
p-value: p=0.002
The predominant pathway for angiotensin II formation in the human heart is through the angiotensin-converting enzyme (ACE), contrary to previous proposals suggesting non-ACE pathways predominate.
Limitations
- Small sample size.
- Majority of patients with heart failure in the in vitro study had previously received ACE-inhibitor therapy, which may have upregulated ACE expression.
- In vivo study patients were on cyclosporin, which may alter Angiotensin I metabolism.
- Concomitant use of aspirin and diuretics in some patients could affect the renin-angiotensin system.
Cite This Study
Zisman et al. (1995) studied Heart transplant recipients and heart failure (n=20). Intracoronary enalaprilat vs. Baseline (without enalaprilat) was evaluated on Fractional conversion of Angiotensin I to Angiotensin II (89% reduction, p=0.002). Intracoronary enalaprilat reduced the fractional conversion of Angiotensin I to Angiotensin II by 89% in the intact human heart, demonstrating that the predominant pathway for Angiotensin II formation is through ACE.