Coronary flow reserve and nitric oxide synthases after cardiac transplantation in humans.
OBJECTIVE
Coronary endothelial dysfunction may precede morphological changes in both the epicardial conduit and microvascular resistance vessels in heart transplant recipients. Since the development of transplant atherosclerosis is the major limiting factor for long-term survival, the identification of early mediators of vasomotor dysfunction may be of therapeutic interest. We therefore investigated the potential relationship between the expression of nitric oxide synthases (NOS) and coronary endothelial function in human cardiac transplant recipients over time.


METHODS
Forty-two human cardiac transplant recipients were studied at 1 and 12 months after heart transplantation (HTx). The microvascular coronary flow velocity reserve (CFVR) was tested for endothelium-dependent (acetylcholine) and -independent (adenosine) stimuli by intravascular Doppler flow-wire. Epicardial diameter changes were evaluated by quantitative coronary angiography. Endomyocardial inducible (iNOS) and endothelial constitutive nitric oxide synthase were determined by RT-PCR. Nitric oxide production (nitrite and nitrate (NOx)) and TNF-alpha were measured in plasma samples from the aorta and coronary sinus.


RESULTS
CFVR was impaired in 26.1% (n=11) of patients at 1 month and in 31% (n=13) 12 months after HTx. iNOS-mRNA levels were significantly higher in patients with impaired endothelium-dependent CFVR. In addition, only in these patients were TNF-alpha levels higher and these correlated with plasma NOx levels at 1 and 12 months post-HTx (1 month: r=0.81, P=0.001; 12 months: r=0.62, P=0.04).


CONCLUSIONS
Coronary microcirculatory dysfunction in response to acetylcholine is present in nearly 30% of patients during the first year following transplantation. These patients present with higher iNOS-mRNA expression and TNF-alpha plasma levels. Selective modulation of the TNF-alpha/iNOS-pathway may be of therapeutic value to improve coronary endothelial dysfunction in cardiac transplant recipients.
Wildhirt
S M
SM
Department of Cardiac Surgery, Ludwig-Maximilians University, Munich, Germany. wildhirt@hch.med.uni-muenchen.de
Weis
M
M
Schulze
C
C
Conrad
N
N
Pehlivanli
S
S
Rieder
G
G
Enders
G
G
von Scheidt
W
W
Reichart
B
B
D000328:Adult; D001783:Blood Flow Velocity / Q000502:physiology; D017023:Coronary Angiography; D003331:Coronary Vessels / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000502:physiology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D016133:Polymerase Chain Reaction; D011184:Postoperative Period; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014666:Vasomotor System / Q000502:physiology*
D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III