Assessing Coronary Endothelial Dysfunction
To the Editor:
Hollenberg and colleagues report that coronary endothelial dysfunction, as detected by abnormal epicardial and microvascular responses to acetylcholine, preceded the development of clinical end points after heart transplantation.1 Similarly, we have shown that coronary endothelial dysfunction has an important effect on prognosis in patients with early coronary atherosclerosis. Although we acknowledge the importance of their findings and their potential clinical impact, we have some reservations about their study methods. The investigators appropriately assessed the microcirculation by measuring the coronary blood flow response to acetylcholine infusion with the use of the Doppler guidewire. The previously validated method for measuring coronary blood flow with the Doppler guidewire involves combining the averaged pulse-wave Doppler velocities with flow, or luminal, area at the site of the Doppler sample volume.2 Flow area is usually calculated from the angiographic diameter measured by use of quantitative coronary angiography methods. In this paper, the investigators measured flow area with intravascular ultrasound (IVUS) at a location “several centimeters” proximal to the Doppler sample volume. Other investigators have validated this method with the assumption that the lumen dimensions are constant along the vessel and that the Doppler measurements are made far enough downstream from the end of the IVUS catheter in which a parabolic velocity profile has reformed.3,4⇓ In the current study, the investigators acknowledged that the wire was placed far distal to the IVUS catheter “to avoid flow artifact from catheter wake.” However, in allograft vasculopathy, one cannot assume that the lumen dimensions will be constant along the length of the vessel, especially during acetylcholine infusion. In patients with early coronary atherosclerosis, the acetylcholine response has been shown to be quite heterogeneous, with adjacent segments having discrepant constrictor and dilator responses.5 Therefore, the flow area at the IVUS catheter site may have been much different from the flow area at the Doppler sample volume. For measurement of absolute coronary blood flow during acetylcholine infusion, we advocate the generally accepted and validated method of combining flow area measured with the use of quantitative coronary angiography methods, rather than simultaneous IVUS and Doppler measurements.
This study greatly adds to the understanding of allograft vasculopathy and we hope this understanding will translate into improved detection, treatment, and prevention of allograft vasculopathy in heart transplant patients.
- ↵Hollenberg SM, Klein LW, Parrillo JE, et al. Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death. Circulation. 2001; 104: 3091–6.
- ↵Doucette JW, Corl PD, Payne HM, et al. Validation of a Doppler guide wire for intravascular measurement of coronary artery flow velocity. Circulation. 1992; 85: 1899–911.
- ↵el-Tamimi H, Mansour M, Wargovich TJ, et al. Constrictor and dilator responses to intracoronary acetylcholine in adjacent segments of the same coronary artery in patients with coronary artery disease. Endothelial function revisited. Circulation. 1994; 89: 45–51.
We appreciate the thoughtful comments of Drs Maniu, Higano, and Lerman. In our study, the Doppler flow wire was positioned several centimeters distal to the terminal portion of the IVUS catheter to avoid artifacts caused by the catheter wake.1 Thus, epicardial area and microvascular flow velocity responses were not obtained at the exact same point in the coronary tree, and this represents an acknowledged limitation of the study, for the reasons outlined in their letter. The methodology does, however, allow for simultaneous assessment of area and flow velocity, allowing for measurement of their time course and maximum response.2 Use of quantitative coronary angiography to measure coronary artery area at the site of the tip of the Doppler has its own limitations, including geometrical assumptions and resolution uncertainties secondary to cardiac motion,3 and although quantitative coronary angiography may be a more accurate method of measuring absolute coronary flow, it does not allow for assessment of the time course of the responses.
Another factor that might mitigate this limitation in our study to some extent is the fact that we expressed our responses as a percentage of baseline for each patient, and thus the error introduced by the different positions would be the same (although heterogeneity in the acetylcholine response could occur, even over the short distance between the IVUS and the Doppler wire). We have analyzed the responses in our study with the use of flow velocity rather than calculated absolute flow, and the conclusions do not change.
- ↵Hollenberg SM, Klein LW, Parrillo JE, et al. Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death. Circulation. 2001; 104: 3091–3096.
- ↵Rosenberg MC, Klein LW, Agarwal JB, et al. Quantification of absolute luminal diameter by computer-analyzed digital subtraction angiography: an assessment in human coronary arteries. Circulation. 1988; 77: 484–490.