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Updated: Oct 10, 2026
A Neonatal Heterotopic Rat Heart Transplantation Model for the Study of Endothelial-to-Mesenchymal Transition
Published on: July 21, 2023
An association between microvascular endothelial dysfunction, transcardiac nitric oxide production and
S M Wildhirt1, M Weis, C Schulze
1Department of Cardiac Surgery, Grosshadern Hospital, Ludwig-Maximilians University, Munich, Germany. wildhirt@hch.med.uni-muenchen.de
Insights
Early after heart transplant (HTx), 26% of patients show impaired microvascular function. This dysfunction is linked to nitric oxide (NO) production and elevated cytokines, suggesting an early target for preventing transplant coronary artery disease (TxCAD).
Area of Science:
- Cardiology
- Immunology
- Transplantation Medicine
Background:
- Endothelial dysfunction precedes transplant coronary artery disease (TxCAD) development over a year post-heart transplantation (HTx).
- Investigating early post-HTx myocardial nitric oxide synthase (NOS) expression and nitric oxide (NO) production is crucial.
- Assessing the relationship between vasomotor function and these early molecular changes is important for TxCAD prevention.
Purpose of the Study:
- To determine if myocardial inducible and constitutive nitric oxide synthases (iNOS; cNOS) are expressed early after HTx.
- To investigate cardiac nitric oxide production in early post-HTx patients.
- To assess the relationship between endothelial and epicardial vasomotor function and these early molecular changes.
Main Methods:
- Studied 42 heart transplant recipients 37 ± 5 days post-HTx.
- Assessed microvascular coronary flow velocity reserve (CFVR) using Doppler flow wire (endothelium-dependent and independent).
- Measured myocardial iNOS/cNOS gene expression, plasma nitrite, and transcardiac cytokine (TNF-α, IL-6) production.
Main Results:
- 26.1% of patients (Group A) exhibited impaired endothelium-dependent CFVR (1.65 ± 0.23 increase).
- Myocardial iNOS/cNOS gene expression did not differ between groups.
- Elevated coronary sinus (CS) levels of TNF-α, IL-6, and nitrite were found in Group A, with CS nitrite correlating with CS TNF-α.
Conclusions:
- Microvascular endothelium-dependent CFVR is impaired in 26% of patients early after HTx.
- Cytokine activation and the NO pathway are implicated in this early vasomotor dysfunction.
- The association between cardiac NO production and TNF-α suggests a chronic inflammatory process, a potential target for TxCAD prevention.
Abstract:
Endothelial dysfunction anticipates the development of transplant coronary artery disease (TxCAD) observed more than 1 year after transplantation (HTx). We investigated whether in patients early after HTx myocardial inducible and constitutive nitric oxide synthases (iNOS; cNOS) are expressed and cardiac nitric oxide production occurs. Moreover, a possible relationship to alterations in endothelium dependent and independent vasomotor function was assessed. Forty-two transplant recipients were studied 37 +/- 5 days after HTx. Microvascular coronary flow velocity reserve (CFVR) was tested endothelium dependent (acetylcholine; 30 microg/min x 5 min/i.c.) and independent (adenosine; 160 microg/min x 5 min/i.c.) by Doppler flow wire. Flow velocity increase by a factor greater than 2 was considered normal. Quantitative coronary angiography was used to assess epicardial vasomotor function in response to the same stimuli. Myocardial iNOS and cNOS gene expression were detected by semiquantitative reversed transcriptase polymerase chain reaction. Plasma nitrite levels (microM) were measured by spectrophotometry. Cytokines (TNF-alpha, IL-6; pg/ml) were measured by enzyme linked immunosorbent assay. In 26.1% of patients (n = 11; group A) an impaired endothelium dependent CFVR (1.65 +/- 0.23 increase) was observed; in 73.9% (n = 31, group B) a normal endothelium dependent CFVR (3.0 +/- 0.7 increase; P = 0.003) was observed. Myocardial iNOS and cNOS gene expression did not differ between the two groups. Transcardiac cytokine production was noted in 58.8% of patients for IL-6 and in 53.3% for TNF-alpha. Coronary sinus (CS) levels of TNF-alpha, IL-6 and nitrite were higher in group A. A significant increase in nitrite production was found only in patients with impaired endothelium dependent CFVR (aorta: 43.9 +/- 3.7 vs CS: 52.8 +/- 5.6, P = 0.05), suggesting transcardiac nitric oxide production. In addition, CS nitrite levels correlated with CS TNF-alpha levels in patients with impaired CFVR (r = 0.44, P = 0.003). Microvascular endothelium dependent CFVR is impaired in 26% of patients early after HTx. Activation of cytokines and the NO pathway seem to be involved in this vasomotor dysfunction The association between cardiac nitric oxide production and TNF-alpha in this group indicates a chronic high immunologic process, which may represent an early and important target for therapy and prevention of TxCAD.
