Coronary Flow Reserve in Cardiac Allograft Vasculopathy

Predictors of reduced coronary flow reserve in heart transplant recipients without angiographically significant coronary artery disease. Transplantation 1999; 68: 1477. Klauss V, Spes CH, Rieber J, Siebert U, Werner F, Stempfle HU, Überfuhr P, Theisen K, Angermann CE, Reichart B, Mudra H. Cardiac transplantation is now an accepted mode of therapy for end-stage heart failure, limited in its applicability only by the shortage of donor organs. There have been many developments in immunosuppression over the last 15 years, and 1-year survival in large centers is approximately 85%. The risk to life after the first year is approximately 4% per year; the most important problems are cardiac allograft vasculopathy (CAV), malignancy, and renal dysfunction (mainly cyclosporine induced). Clinically important CAV is unusual in the first 5 years after transplantation but is increasingly common thereafter. Surveillance coronary angiography in the 1970s and 1980s established the prevalence and natural history of CAV (1), but necropsy studies showed that angiography underestimated the extent of disease because of its distal and diffuse nature. With the advent of intravascular ultrasound (IVUS), it became apparent that intimal thickening developed in most patients as early as the first year in spite of angiographically normal coronary arteries (2). In one study, investigators found that although 80% of coronary segments demonstrated intimal thickening by IVUS, only 10% of these were abnormal on routine angiography. The presence of moderate to severe intimal thickening has been shown to be predictive of the future development of angiographic CAV (3) and cardiac events. The concept of coronary flow reserve (CFR) was introduced by Gould et al. (4) and is defined as the ratio of maximal to resting coronary blood flow. It represents the ability of coronary blood flow to increase when metabolic requirements demand it. The main resistance to coronary blood flow lies in small intramural arteries that are beyond the resolution of coronary angiography. The diffuse nature of CAV has led investigators to apply CFR measurements to its study. The development of Doppler-tipped catheters and flow wires have made the technique easier, and it can be combined with coronary angiography without greatly adding to the time needed for the study. Maximal blood flow is measured after vasodilatation with an endothelium-independent dilator, usually adenosine, administered into the coronary artery. CFR has been shown to be preserved in the first 2 years after cardiac transplantation, but conflicting results have been reported in long-term studies. McGinn et al. (5) demonstrated that in the absence of allograft rejection, ventricular hypertrophy, and regional wall motion abnormalities, CFR is normal in transplanted hearts despite mild to moderate CAV. Mullins et al. (6), however, found that some patients with angiographically normal or minimally diseased vessels had a low CFR. A recent study suggests that patients with a low CFR (<2.5) are more likely to develop ventricular dysfunction despite angiographically normal coronary arteries (7). Combined IVUS and Doppler flow studies have shown that the degree of intimal thickening in epicardial arteries does not correlate with the adenosine-induced hyperemic response. This suggests that epicardial and intramural arteries may be affected to different degrees and that IVUS and CFR studies may provide independent prognostic information. The study by Klauss et al. in the current issue of the journal studied 60 patients at varying intervals after cardiac transplantation. Ventricular ejection fraction was normal in all patients, left ventricular hypertrophy was present in 17 patients, and no patient had significant rejection on endomyocardial biopsy. Coronary angiography showed normal or minimally diseased coronary arteries. CFR was lower in patients with higher donor age and left ventricular hypertrophy. In both these groups, CFR was reduced due to an elevated baseline flow velocity rather than a low maximal flow velocity. As the authors have reported in a previous study, CFR did not correlate with intimal thickening demonstrated on IVUS. The association of a decreased CFR with left ventricular hypertrophy has been described in other studies; total resting flow is increased but maximal flow per gram of tissue is unaltered. The development of increasingly sophisticated techniques to study coronary structure and physiology has undoubtedly contributed to our understanding of the nature of CAV. The treatment of CAV, however, has not advanced significantly; most patients do not suffer angina, and symptomatic therapy with anti-anginal drugs is usually not indicated. The diffuse nature of the disease makes revascularization by angioplasty or bypass surgery impossible in most patients. Retransplantation remains the only definitive treatment but cannot be widely applied because of the shortage of donor organs and the worse prognosis in this group of patients. Under the circumstances it can be argued that techniques like IVUS and CFR measurement are not justified in routine clinical practice because of the expense involved. Studies of new treatments that might affect the onset or progression of CAV, however, need end points other than angiographic disease because the latter is relatively insensitive. IVUS to study epicardial conduit vessels and CFR measurement to study resistance vessel function are useful adjuncts in these circumstances.