Response to: Labarrere CA et al. (2009) C-reactive protein and severity of coronary allograft vasculopathy. Nat Clin Pract Cardiovasc Med [doi:ncpcardio1473]

Arising from: Sarno G et al. (2008) Multicenter assessment of coronary allograft vasculopathy by intravascular ultrasound-derived analysis of plaque composition. Nat Clin Pract Cardiovasc Med 6: 61–69 [doi:10.1038/ncpcardio1410]

We thank Dr Labarrere and colleagues for their discussion of the pivotal findings described in our paper on the assessment of coronary allograft vasculopathy by virtual histology-intravascular ultrasound (VH-IVUS).1 In our study, plaque composition detected by VH-IVUS shows dynamic changes over time. Time-dependent increases in the content of the necrotic core are most apparent. This finding has important clinical implications, because coronary revascularization was required among patients whose plaques had a large necrotic core.

In contrast to the findings of previous studies, we did not observe any association between the conventional cardiovascular risk factors—such as diabetes, smoking, or hypertension—and plaque composition or burden. In our study, C-reactive protein (CRP) levels were not correlated with necrotic core content, and no significant differences in CRP levels were found between patients undergoing revascularization and those not undergoing revascularization. As suggested by Hognestad et al.,2 CRP levels in heart transplant patients can be strongly affected by different doses of corticosteroids, immunosuppressive drugs, and statins.

We agree with Labarrere et al.3 that elevated plasma levels of CRP are associated with angiographic evidence of coronary allograft vasculopathy (CAV), and that a rise in CRP during follow-up is a strong predictor for the development of CAV. However, looking carefully at their findings on the relationship between angiographic CAV severity and CRP levels, we could remark that only 54.5% of patients with severe CAV showed high CRP levels, while 45.5% of patients with severe CAV showed low levels of CRP.3 Moreover, in the article by Hognestad et al.,2 CRP level is identified only as an independent predictor of CAV angiographic evidence and there is no multiple comparison test showing a significant difference among patients with mild, moderate, or severe CAV.

The upregulation of adhesion molecules in the arterial and arteriolar endothelium, as well as the presence of elevated soluble inter-cellular adhesion molecule 1 in the circulation, indicate that CAV is not only limited to the epicardial arteries, but also compromises the small intramyocardial arteries and arterioles. As we have acknowledged in our article,1 VH-IVUS is limited to the study of the proximal-segments and mid-segments of epicardial coronary arteries and does not, therefore, provide any diagnostic information regarding the impairment of the microvasculature. However, Fearon et al.4 have shown that among asymptomatic patients with CAV, the percent of maximum achievable flow in the epicardial artery, as measured by fractional flow reserve, decreased during the first year after transplantation. This decrease was the result of a combination of increased plaque burden and decreased vessel volume (negative remodeling), as measured by IVUS. By contrast, the minimum achievable microvascular resistance, as measured by the index of microvascular resistance, decreased significantly (i.e. microvascular physiology improved) during this first year. The same group5 has also investigated the timing of the development of abnormalities in the epicardial and microvascular arteries. Early after heart transplantation, anatomical and physiological evidence of epicardial CAV was found, while later after transplantation, the physiological effect of epicardial CAV was reduced, because of increased microvascular dysfunction.5 Serial VH-IVUS assessments could be used to investigate the relationship between early levels of proinflammatory molecules, such as CRP, and changes in plaque burden and composition over time. Prospective studies addressing these issues are of the utmost importance.